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10,883	MYAMBUTOL (ethambutol hcl) tablets DESCRIPTION MYAMBUTOL ethambutol hydrochloride is an oral chemotherapeutic agent which is specifically effective against actively growing microorganisms of the genus Mycobacterium, including M. tuberculosis. The structural formula is: Chemical Structure MYAMBUTOL 100 and 400 mg tablets contain the following inactive ingredients: Gelatin, Hydroxypropyl Methylcellulose, Magnesium Stearate, Sodium Lauryl Sulfate, Sorbitol, Stearic Acid, Sucrose, Titanium Dioxide and other ingredients. CLINICAL PHARMACOLOGY MYAMBUTOL, following a single oral dose of 25 mg/kg of body weight, attains a peak of 2 to 5 mcg/mL in serum 2 to 4 hours after administration. When the drug is administered daily for longer periods of time at this dose, serum levels are similar. The serum level of MYAMBUTOL falls to undetectable levels by 24 hours after the last dose except in some patients with abnormal renal function. The intracellular concentrations of erythrocytes reach peak values approximately twice those of plasma and maintain this ratio throughout the 24 hours. During the 24-hour period following oral administration of MYAMBUTOL approximately 50 percent of the initial dose is excreted unchanged in the urine, while an additional 8 to 15 percent appears in the form of metabolites. The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. From 20 to 22 percent of the initial dose is excreted in the feces as unchanged drug. No drug accumulation has been observed with consecutive single daily doses of 25 mg/kg in patients with normal kidney function, although marked accumulation has been demonstrated in patients with renal insufficiency. MYAMBUTOL diffuses into actively growing Mycobacterium cells such as tubercle bacilli. MYAMBUTOL appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated. MYAMBUTOL has been shown to be effective against strains of Mycobacterium tuberculosis but does not seem to be active against fungi, viruses, or other bacteria. Mycobacterium tuberculosis strains previously unexposed to MYAMBUTOL have been uniformly sensitive to concentrations of 8 or less mcg/mL, depending on the nature of the culture media. When MYAMBUTOL has been used alone for treatment of tuberculosis, tubercle bacilli from these patients have developed resistance to MYAMBUTOL (ethambutol hydrochloride) by in-vitro susceptibility tests; the development of resistance has been unpredictable and appears to occur in a step- like manner. No cross resistance between MYAMBUTOL and other antituberculous drugs has been reported. MYAMBUTOL has reduced the incidence of the emergence of mycobacterial resistance to isoniazid when both drugs have been used concurrently. An agar diffusion microbiologic assay, based upon inhibition of Mycobacterium smegmatis (ATCC 607) may be used to determine concentrations of MYAMBUTOL in serum and urine. ANIMAL PHARMACOLOGY Toxicological studies in dogs on high prolonged doses produced evidence of myocardial damage and failure, and depigmentation of the tapetum lucidum of the eyes, the significance of which is not known. Degenerative changes in the central nervous system, apparently not dose-related, have also been noted in dogs receiving ethambutol hydrochloride over a prolonged period. In the rhesus monkey, neurological signs appeared after treatment with high doses given daily over a period of several months. These were correlated with specific serum levels of ethambutol and with definite neuroanatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received ethambutol hydrochloride in high doses for a prolonged period. INDICATIONS MYAMBUTOL is indicated for the treatment of pulmonary tuberculosis. It should not be used as the sole antituberculous drug, but should be used in conjunction with at least one other antituberculous drug. Selection of the companion drug should be based on clinical experience, considerations of comparative safety, and appropriate in-vitro susceptibility studies. In patients who have not received previous antituberculous therapy, ie, initial treatment, the most frequently used regimens have been the following: MYAMBUTOL plus isoniazid MYAMBUTOL plus isoniazid plus streptomycin. page 1 of 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients who have received previous antituberculous therapy, mycobacterial resistance to other drugs used in initial therapy is frequent. Consequently, in such retreatment patients, MYAMBUTOL should be combined with at least one of the second line drugs not previously administered to the patient and to which bacterial susceptibility has been indicated by appropriate in-vitro studies. Antituberculous drugs used with MYAMBUTOL have included cycloserine, ethionamide, pyrazinamide, viomycin and other drugs. Isoniazid, aminosalicylic acid, and streptomycin have also been used in multiple drug regimens. Alternating drug regimens have also been utilized. CONTRAINDICATIONS MYAMBUTOL is contraindicated in patients who are known to be hypersensitive to this drug. It is also contraindicated in patients with known optic neuritis unless clinical judgment determines that it may be used. MYAMBUTOL is contraindicated in patients who are unable to appreciate and report visual side effects or changes in vision (e.g., young children, unconscious patients). WARNINGS MYAMBUTOL may produce decreases in visual acuity which appear to be due to optic neuritis. This effect may be related to dose and duration of treatment. This effect is generally reversible when administration of the drug is discontinued promptly. However, irreversible blindness has been reported. (See PRECAUTIONS and ADVERSE REACTIONS). Liver toxicities including fatalities have been reported (see ADVERSE REACTIONS). Baseline and periodic assessment of hepatic function should be performed. PRECAUTIONS MYAMBUTOL ethambutol hydrochloride is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. Patients with decreased renal function need the dosage reduced as determined by serum levels of MYAMBUTOL, since the main path of excretion of this drug is by the kidneys. Because this drug may have adverse effects on vision, physical examination should include ophthalmoscopy, finger perimetry and testing of color discrimination. In patients with visual defects such as cataracts, recurrent inflammatory conditions of the eye, optic neuritis, and diabetic retinopathy, the evaluation of changes in visual acuity is more difficult, and care should be taken to be sure the variations in vision are not due to the underlying disease conditions. In such patients, consideration should be given to relationship between benefits expected and possible visual deterioration since evaluation of visual changes is difficult. (For recommended procedures, see next paragraphs under ADVERSE REACTIONS.) As with any potent drug, baseline and periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, should be performed. Drug Interactions The results of a study of coadministration of MYAMBUTOL (50mg/kg) with an aluminum hydroxide containing antacid to 13 patients with tuberculosis showed a reduction of mean serum concentrations and urinary excretion of ethambutol of approximately 20% and 13%, respectively, suggesting that the oral absorption of ethambutol may be reduced by these antacid products. It is recommended to avoid concurrent administration of ethambutol with aluminum hydroxide containing antacids for at least 4 hours following ethambutol administration. Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. There are reports of ophthalmic abnormalities occurring in infants born to women on antituberculous therapy that included MYAMBUTOL. MYAMBUTOL should be used during pregnancy only if the benefit justifies the potential risk to the fetus. MYAMBUTOL has been shown to be teratogenic in pregnant mice and rabbits when given in high doses. When pregnant mice or rabbits were treated with high doses of ethambutol hydrochloride, fetal mortality was slightly but not significantly (P>0.05) increased. Female rats treated with ethambutol hydrochloride displayed slight but insignificant (P>0.05) decreases in fertility and litter size. In fetuses born of mice treated with high doses of MYAMBUTOL during pregnancy, a low incidence of cleft palate, exencephaly and abnormality of the vertebral column were observed. Minor abnormalities of the cervical vertebra were seen in the newborn of rats treated with high doses of ethambutol hydrochloride during pregnancy. Rabbits receiving high doses of MYAMBUTOL during pregnancy gave birth to two fetuses with monophthalmia, one with a shortened right forearm accompanied by bilateral wrist-joint contracture and one with hare lip and cleft palate. page 2 of 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers MYAMBUTOL is excreted into breast milk. The use of MYAMBUTOL should be considered only if the expected benefit to the mother outweighs the potential risk to the infant. Pediatric Use MYAMBUTOL (ethambutol hydrochloride) is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. Geriatric Use There are limited data on the use of MYAMBUTOL in the elderly. One study of 101 patients, 65 years and older, on multiple drug antituberculosis regimens included 94 patients on MYAMBUTOL. No differences in safety or tolerability were observed in these patients compared with that reported in adults in general. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS MYAMBUTOL may produce decreases in visual acuity, including irreversible blindness, which appear to be due to optic neuritis. Optic neuropathy including optic neuritis or retrobulbar neuritis occurring in association with ethambutol therapy may be characterized by one or more of the following events: decreased visual acuity, scotoma, color blindness, and/or visual defect. These events have also been reported in the absence of a diagnosis of optic or retrobulbar neuritis. Patients should be advised to report promptly to their physician any change of visual acuity. The change in visual acuity may be unilateral or bilateral and hence each eye must be tested separately and both eyes tested together. Testing of visual acuity should be performed before beginning MYAMBUTOL therapy and periodically during drug administration, except that it should be done monthly when a patient is on a dosage of more than 15 mg per kilogram per day. Snellen eye charts are recommended for testing of visual acuity. Studies have shown that there are definite fluctuations of one or two lines of the Snellen chart in the visual acuity of many tuberculous patients not receiving MYAMBUTOL. The following table may be useful in interpreting possible changes in visual acuity attributable to MYAMBUTOL. Initial Reading Significant Decrease Snellen Indicating Number Number Reading Significant of Lines of Points Decrease 20/13 20/25 3 12 20/15 20/25 2 10 20/20 20/30 2 10 20/25 20/40 2 15 20/30 20/50 2 20 20/40 20/70 2 30 20/50 20/70 1 20 In general, changes in visual acuity less than those indicated under “Significant Number of Lines” and “Decrease Number of Points” may be due to chance variation, limitations of the testing method, or physiologic variability. Conversely, changes in visual acuity equaling or exceeding those under “Significant Number of Lines” and “Decrease Number of Points” indicate need for retesting and careful evaluation of the patient's visual status. If careful evaluation confirms the magnitude of visual change and fails to reveal another cause, MYAMBUTOL should be discontinued and the patient reevaluated at frequent intervals. Progressive decreases in visual acuity during therapy must be considered to be due to MYAMBUTOL. If corrective glasses are used prior to treatment, these must be worn during visual acuity testing. During 1 to 2 years of therapy, a refractive error may develop which must be corrected in order to obtain accurate test results. Testing the visual acuity through a pinhole eliminates refractive error. Patients developing visual abnormality during MYAMBUTOL treatment may show subjective visual symptoms before, or simultaneously with, the demonstration of decreases in visual acuity, and all patients receiving MYAMBUTOL should be questioned periodically about blurred vision and other subjective eye symptoms. Recovery of visual acuity generally occurs over a period of weeks to months after the drug has been discontinued. Some patients have received MYAMBUTOL (ethambutol hydrochloride) again after such recovery without recurrence of loss of visual acuity. Other adverse reactions reported include: hypersensitivity, anaphylactic/anaphylactoid reaction, dermatitis, erythema multiforme, pruritus, and joint pain; anorexia, nausea, vomiting, gastrointestinal upset, and abdominal pain; fever, malaise, headache, and dizziness; mental confusion, disorientation, and possible hallucinations; thrombocytopenia, leucopenia, and neutropenia. Numbness and tingling of page 3 of 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the extremities due to peripheral neuritis have been reported. Elevated serum uric acid levels occur and precipitation of acute gout has been reported. Pulmonary infiltrates, with or without eosinophilia, also have been reported during MYAMBUTOL therapy. Liver toxicities, including fatalities, have been reported. (See WARNINGS). Since MYAMBUTOL is recommended for therapy in conjunction with one or more other antituberculous drugs, these changes may be related to the concurrent therapy. Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis. Fever and lymphadenopathy may be present. DOSAGE AND ADMINISTRATION MYAMBUTOL should not be used alone, in initial treatment or in retreatment. MYAMBUTOL should be administered on a once every 24-hour basis only. Absorption is not significantly altered by administration with food. Therapy, in general, should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occurred. MYAMBUTOL is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. Initial Treatment: In patients who have not received previous antituberculous therapy, administer MYAMBUTOL 15 mg/kg (7 mg/ lb) of body weight, as a single oral dose once every 24 hours. In the more recent studies, isoniazid has been administered concurrently in a single, daily, oral dose. Retreatment: In patients who have received previous antituberculous therapy, administer MYAMBUTOL 25 mg/kg (11 mg/lb) of body weight, as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculous drug to which the organisms have been demonstrated to be susceptible by appropriate in-vitro tests. Suitable drugs usually consist of those not previously used in the treatment of the patient. After 60 days of MYAMBUTOL administration, decrease the dose to 15 mg/kg (7mg/ lb) of body weight, and administer as a single oral dose once every 24 hours. During the period when a patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised. See Table for easy selection of proper weight-dose tablet(s). Weight-Dose Table 15 mg/kg (7 mg/lb) Schedule Weight Range Dose Pounds Kilograms In mg Under 85 lbs Under 37 Kg .................... 500 85 – 94.5 37 – 43 ........................... 600 95 – 109.5 43 – 50 ............................700 110– 124.5 50 – 57 ........................... 800 125– 139.5 57 – 64 ........................... 900 140– 154.5 64 – 71 ......................... 1000 155– 169.5 71 – 79 ......................... 1100 170 – 184.5 79 – 84 ......................... 1200 185– 199.5 84 – 90 ......................... 1300 200– 214.5 90 – 97 ......................... 1400 215 and Over Over 97 ......................... 1500 25 mg/kg (11 mg/lb) Schedule Under 85 lbs. Under 38 kg .. ............... 900 85 – 92.5 38 – 42 ........................ 1000 93 – 101.5 42 – 45.5 ..................... 1100 102– 109.5 45.5 – 50 ..................... 1200 110– 118.5 50 – 54 ........................ 1300 119– 128.5 54 – 58 ........................ 1400 129– 136.5 58 – 62 ........................ 1500 137– 146.5 62 – 67 ........................ 1600 147–155.5 67 – 71 ........................ 1700 page 4 of 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 156– 164.5 71 – 75 ........................ 1800 165– 173.5 75 – 79 ........................ 1900 174– 182.5 79 – 83 ........................ 2000 183– 191.5 83 – 87 ........................ 2100 192– 199.5 87 – 91 ........................ 2200 200– 209.5 91 – 95 ........................ 2300 210– 218.5 95 – 99 ........................ 2400 219 and Over Over 99 ....................... 2500 HOW SUPPLIED MYAMBUTOL® (Ethambutol Hydrochloride) Tablets USP 100 mg – round, convex, white, film coated tablets engraved M6 on one side are supplied as follows: NDC 68850-010-01 - Bottle of 100 400 mg – round, convex, white, scored, film coated tablets engraved with M to the left and 7 to the right of the score on one side are supplied as follows: NDC 68850-012-01 - Bottle of 100 NDC 68850-012-03 - Bottle of NDC 68850-012-02 - 10 Blister-packs x 10 tablets 1000 Store at controlled room temperature 20° to 25°C (68° to 77°F). Manufactured by Patheon Inc. Toronto, Ontario, Canada. For Stat-Trade, Inc. Distributed by X-GEN Pharmaceuticals, Inc., Northport, NY 11768. Myambutol is a registered trademark of Stat-Trade, Inc. © 2004 Stat-Trade, Inc. Revised January 2007 LB-10976/Y page 5 of 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:58.969317	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/016320s063lbl.pdf', 'application_number': 16320, 'submission_type': 'SUPPL ', 'submission_number': 63}
10,885	NDA 16-324/S-031 NDA 17-391/S-014 Page 3 PRODUCT INFORMATION Imuran® (azathioprine) 50-mg Scored Tablets 100 mg (as the sodium salt) for I.V. injection, Equivalent to 100 mg azathioprine sterile lyophilized material. Rx only WARNING: Chronic immunosuppression with this purine antimetabolite increases risk of neoplasia in humans. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. See WARNINGS. DESCRIPTION: IMURAN (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration and 100-mg vials for intravenous injection. Each scored tablet contains 50 mg azathioprine and the inactive ingredients lactose, magnesium stearate, potato starch, povidone, and stearic acid. Each 100-mg vial contains azathioprine, as the sodium salt, equivalent to 100 mg azathioprine sterile lyophilized material and sodium hydroxide to adjust pH. Azathioprine is chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. The structural formula of azathioprine is: Chemical Structure It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound. Azathioprine is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. The sodium salt of azathioprine is sufficiently soluble to make a 10mg/mL water solution which is stable for 24 hours at 59° to 77°F (15° to 25°C). Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide. CLINICAL PHARMACOLOGY: Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35 S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable. See OVERDOSAGE. Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 4 urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6 TGNs) as major metabolites (See Metabolism Scheme in Figure 1). The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA. 6-MP undergoes two major inactivation routes ( Figure 1). One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). TPMT activity is controlled by a genetic polymorphism. 1,2,3 For Caucasians and African Americans, approximately 10% of the population inherit one non-functional TPMT allele (heterozygous) conferring intermediate TPMT activity, and 0.3% inherit two TPMT non-functional alleles (homozygous) for low or absent TPMT activity. Non-functional alleles are less common in Asians. TPMT activity correlates inversely with 6 TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities, leaving TPMT methylation as the only inactivation pathway. Patients with intermediate TPMT activity may be at increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN.4-9 TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing IMURAN toxicity.2, 3, 7, 8, 9 Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. See WARNINGS, PRECAUTIONS: Drug Interactions, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections. Metabolism pathway Chart Figure 1. Metabolism pathway of azathioprine: competing pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA. GMPS: Guanosine monophosphate synthetase; HGPRT: Hypoxanthine-guanine-phosphoribosyl-transferase; IMPD: Inosine monophosphate dehydrogenase; MeMP: Methylmercaptopurine; MeMPN: Methylmercaptopurine nucleotide; TGN: Thioguanine nucleotides; TIMP: Thioinosine monophosphate; TPMT: Thiopurine S-methyltransferase; TU Thiouric acid; XO: Xanthine oxidase) (Adapted from Pharmacogenomics 2002; 3:89-98; and Cancer Res 2001; 61:5810-5816.) Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The inhibition of xanthine oxidase in patients receiving allopurinol (ZYLOPRIM®) is the basis for the azathioprine dosage reduction required in these patients (see PRECAUTIONS: Drug Interactions). Proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function. Homograft Survival: The use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graft rejections or secondary responses. Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by azathioprine. These patients have subnormal responses to vaccines, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 5 low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody responses are usually normal. Immunoinflammatory Response: Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine. The mechanisms whereby azathioprine affects autoimmune diseases are not known. Azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia, which precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued. INDICATIONS AND USAGE: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms. Renal Homotransplantation: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables. The effect of IMURAN on these variables has not been tested in controlled trials. Rheumatoid Arthritis: IMURAN is indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms. Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with IMURAN. The combined use of IMURAN with disease modifying anti rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of IMURAN with these agents cannot be recommended. CONTRAINDICATIONS: IMURAN should not be given to patients who have shown hypersensitivity to the drug. IMURAN should not be used for treating rheumatoid arthritis in pregnant women. Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of neoplasia if treated with IMURAN. WARNINGS: Severe leukopenia, thrombocytopenia, macrocytic anemia, and/or pancytopenia may occur in patients being treated with IMURAN. Severe bone marrow suppression may also occur. Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing IMURAN toxicity. 2-9 (See PRECAUTIONS: Laboratory Tests). Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection. It is suggested that patients on IMURAN have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count. Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients. Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs should be considered. IMURAN is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient's risk of neoplasia. Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 6 patients who receive aggressive treatment with immunosuppressive drugs. The degree of immunosuppression is determined, not only by the immunosuppressive regimen, but also by a number of other patient factors. The number of immunosuppressive agents may not necessarily increase the risk of post-transplant lymphomas. However, transplant patients who receive multiple immunosuppressive agents may be at risk for over- immunosuppression; therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. Information is available on the spontaneous neoplasia risk in rheumatoid arthritis, and on neoplasia following immunosuppressive therapy of other autoimmune diseases. It has not been possible to define the precise risk of neoplasia due to IMURAN. The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients. However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine. Data on neoplasia in patients receiving IMURAN can be found under ADVERSE REACTIONS. IMURAN has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose;10 a reduced percentage of fertile matings occurred when animals received 5 mg/kg. 11 Pregnancy: Pregnancy Category D. IMURAN can cause fetal harm when administered to a pregnant woman. IMURAN should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of IMURAN in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. 12 IMURAN is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies. 11 Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on IMURAN. In a detailed case report, 13 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily. 14 There have been two published reports of abnormal physical findings. Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy. 15 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus. The father was on long-term azathioprine therapy. 16 Benefit versus risk must be weighed carefully before use of IMURAN in patients of reproductive potential. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant. PRECAUTIONS: General: A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of therapy with IMURAN and are reversible upon discontinuation of the drug. The reaction can recur within hours after re-challenge with a single dose of IMURAN. Information for Patients: Patients being started on IMURAN should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. They should be informed of the danger of infection while receiving IMURAN and asked to report signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient, especially when IMURAN is being administered in the presence of impaired renal function or concomitantly with allopurinol (see Drug Interactions subsection and DOSAGE AND ADMINISTRATION). Patients should be advised of the potential risks of the use of IMURAN during pregnancy and during the nursing period. The increased risk of neoplasia following therapy with IMURAN should be explained to the patient. Laboratory Tests: Complete Blood Count (CBC) Monitoring: Patients on IMURAN should have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 7 months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. TPMT Testing: It is recommended that consideration be given to either genotype or phenotype patients for TPMT. Phenotyping and genotyping methods are commercially available. The most common non-functional alleles associated with reduced levels of TPMT activity are TPMT2, TPMT3A and TPMT3C. Patients with two non-functional alleles (homozygous) have low or absent TPMT activity and those with one non-functional allele (heterozygous) have intermediate activity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. TPMT testing may also be considered in patients with abnormal CBC results that do not respond to dose reduction. Early drug discontinuation in these patients is advisable. TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections. Drug Interactions: Use with Allopurinol: One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN, to approximately 1/3 to 1/4 the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving IMURAN and allopurinol because both TPMT and XO inactivation pathways are affected. See CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections. Use with Aminosalicylates: There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with IMURAN should be done with caution. Use with Other Agents Affecting Myelopoesis: Drugs which may affect leukocyte production, including co trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients. Use with Angiotensin-Converting Enzyme Inhibitors: The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia. Use with Warfarin: IMURAN may inhibit the anticoagulant effect of warfarin. Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section. Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section. Nursing Mothers: The use of IMURAN in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. 17, 18, 19 Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and efficacy of azathioprine in pediatric patients have not been established. ADVERSE REACTIONS: The principal and potentially serious toxic effects of IMURAN are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see WARNINGS). The frequency and severity of adverse reactions depend on the dose and duration of IMURAN as well as on the patient's underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing IMURAN for rheumatoid arthritis. The relative incidences in clinical studies are summarized below: Renal Rheumatoid Toxicity Homograft Arthritis Leukopenia (any degree) >50% 28% <2500 cells/mm3 16% 5.3% Infections 20% <1% Neoplasia Lymphoma 0.5% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 8 Others 2.8% * Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg per day) was 1.8 cases per 1000 patient- years of follow-up, compared with 0.8 cases per 1000 patient-years of follow-up in those not receiving azathioprine. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined. Hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with IMURAN. Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Macrocytic anemia and/or bleeding have been reported. TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for non-functional alleles) who are at increased risk for severe, life-threatening myelosuppression from IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS: Laboratory Tests. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine.6, 20 Gastrointestinal: Nausea and vomiting may occur within the first few months of therapy with IMURAN, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of IMURAN. A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving IMURAN for panuveitis.21, 22, 23 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, IMURAN should be permanently withdrawn. Others: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, reversible interstitial pneumonitis and hepatosplenic T-cell lymphoma. OVERDOSAGE: The oral LD50s for single doses of IMURAN in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. About 30% of IMURAN is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis.24 A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg IMURAN. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose. DOSAGE AND ADMINISTRATION: TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity from IMURAN if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non functional alleles). IMURAN should be administered with caution to patients having one non-functional allele This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 9 (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction. Renal Homotransplantation: The dose of IMURAN required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. IMURAN is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. IMURAN is often initiated with the intravenous administration of the sodium salt, with subsequent use of tablets (at the same dose level) after the postoperative period. Intravenous administration of the sodium salt is indicated only in patients unable to tolerate oral medications. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of IMURAN should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal. Rheumatoid Arthritis: IMURAN is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. IMURAN may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities. Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance IMURAN has not been determined. IMURAN can be discontinued abruptly, but delayed effects are possible. Use in Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of IMURAN or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses. Parenteral Administration: Add 10 mL of Sterile Water for Injection, and swirl until a clear solution results. This solution, equivalent to 100 mg azathioprine, is for intravenous use only; it has a pH of approximately 9.6, and it should be used within 24 hours. Further dilution into sterile saline or dextrose is usually made for infusion; the final volume depends on time for the infusion, usually 30 to 60 minutes, but as short as 5 minutes and as long as 8 hours for the daily dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published.25-31 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. HOW SUPPLIED: 50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with “IMURAN” and “50” on each tablet; bottle of 100 (NDC 65483-590-10). Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light. 20-mL vial, each containing the equivalent of 100 mg azathioprine (as the sodium salt) (NDC 65483-551-01). Store at 15° to 25°C (59° to 77°F) and protect from light. The sterile, lyophilized sodium salt is yellow, and should be dissolved in Sterile Water for Injection (see DOSAGE AND ADMINISTRATION: Parenteral Administration). REFERENCES: 1. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43:329-339. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 10 2. Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos. 2001;29:601-605. 3. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3:89-98. 4. Anstey A, Lennard L, Mayou SC, et al. Pancytopenia related to azathioprine – an enzyme deficiency caused by a common genetic polymorphism: a review. JR Soc Med. 1992; 85:752-756. 5. Stolk JN, Beorbooms AM, de Abreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998; 41:1858-1866. 6. Data on file, Prometheus Laboratories Inc. 7. Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997; 126:608-614. 8. Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy- limiting severe toxicity from azathioprine. Ann Intern Med. 1998; 129:716-718. 9. Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology. 2004; 43:13-18. 10. Clark JM. The mutagenicity of azathioprine in mice, Drosophila melanogaster, and Neurospora crassa. Mutat Res. 1975; 28:87-99. 11. Data on file, Prometheus Laboratories Inc. 12. Tagatz GE, Simmons RL. Pregnancy after renal transplantation. Ann Intern Med. 1975; 82:113-114. Editorial Notes. 13. Cote' CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr. 1974; 85:324-328. 14. DeWitte DB, Buick MK, Cyran SE, et al. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. J Pediatr. 1984; 105:625-628. 15. Williamson RA, Karp LE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol. 1981; 58:247-250. 16. Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA. 1970; 211: 1854-1855. 17. Data on file, Prometheus Laboratories Inc. 18. Saarikoski S, Seppälä M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol. 1973; 115:1100-1106. 19. Coulam CB, Moyer TP, Jiang NS, et al. Breast-feeding after renal transplantation. Transplant Proc. 1982; 14: 605-609. 20. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant patients. Lancet. 1993; 341:436. 21. Read AE, Wiesner RH, LaBrecque DR, et al. Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med. 1986; 104:651-655. 22. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic veno-occlusive disease in renal transplant patients. Gastroenterology. 1986; 90:446-454. 23. Weitz H, Gokel JM, Loeshke K, et al. Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch A Pathol Anat Histol. 1982; 395:245-256. 24. Schusziarra V, Ziekursch V, Schlamp R, et al. Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol Biopharm. 1976; 14:298-302. 25. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institute of Health; 1992. US Dept of Health and Human Services. Public Health Service Publication NIH 92-2621. 26. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985; 253:1590-1592. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 11 27. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 28. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983; 1:426-428. 29. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J for Clinicians. 1983; 33:258-263. 30. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049. 31. Yodaiken RE, Bennett D. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm, 1996; 43:1193-1204. PROMETHEUS LABORATORIES INC. Manufactured by DSM Pharmaceuticals, Inc. Greenville, NC 27834 for Prometheus Laboratories Inc. San Diego, CA 92121 May 2008 IM005G08 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:59.134530	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/016324s031,017391s014lbl.pdf', 'application_number': 16324, 'submission_type': 'SUPPL ', 'submission_number': 31}
10,886	PRODUCT INFORMATION ® IMURAN (azathioprine) 50-mg Scored Tablets Rx only WARNING - MALIGNANCY Chronic immunosuppression with IMURAN, a purine antimetabolite increases risk of malignancy in humans. Reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. Physicians should inform patients of the risk of malignancy with IMURAN. See WARNINGS. DESCRIPTION: IMURAN (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration. Each scored tablet contains 50 mg azathioprine and the inactive ingredients lactose, magnesium stearate, potato starch, povidone, and stearic acid. Azathioprine is chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. The structural formula of azathioprine is: structural formula It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound. Azathioprine is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide. CLINICAL PHARMACOLOGY: Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable. See OVERDOSAGE. Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major 1 Reference ID: 2951014 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda f l o w chart IMURAN ® (azathioprine) metabolites (See Metabolism Scheme in Figure 1). The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA. 6-MP undergoes two major inactivation routes (Figure 1). One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). TPMT activity is controlled by a genetic polymorphism.1, 2, 3 For Caucasians and African Americans, approximately 10% of the population inherit one non-functional TPMT allele (heterozygous) conferring intermediate TPMT activity, and 0.3% inherit two TPMT non-functional alleles (homozygous) for low or absent TPMT activity. Non-functional alleles are less common in Asians. TPMT activity correlates inversely with 6-TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities, leaving TPMT methylation as the only inactivation pathway. Patients with intermediate TPMT activity may be at increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN.4-9 TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing IMURAN toxicity.2, 3, 7, 8, 9 Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. See WARNINGS, PRECAUTIONS: Drug Interactions, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections. Figure 1. Metabolism pathway of azathioprine: competing pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA. GMPS: Guanosine monophosphate synthetase; HGPRT: Hypoxanthine-guanine-phosphoribosyl-transferase; IMPD: Inosine monophosphate dehydrogenase; MeMP: Methylmercaptopurine; MeMPN: Methylmercaptopurine nucleotide; TGN: Thioguanine nucleotides; TIMP: Thioinosine monophosphate; TPMT: Thiopurine S-methyltransferase; TU Thiouric acid; XO: Xanthine oxidase (Adapted from Pharmacogenomics 2002; 3:89-98; and Cancer Res 2001; 61:5810-5816.) Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The inhibition of xanthine oxidase in patients receiving allopurinol (ZYLOPRIM®) is the basis for the azathioprine dosage reduction required in these patients (see PRECAUTIONS: Drug Interactions). Proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function. Homograft Survival: The use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell 2 Reference ID: 2951014 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IMURAN ® (azathioprine) suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graft rejections or secondary responses. Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by azathioprine. These patients have subnormal responses to vaccines, low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody responses are usually normal. Immunoinflammatory Response: Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine. The mechanisms whereby azathioprine affects autoimmune diseases are not known. Azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia, which precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued. INDICATIONS AND USAGE: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms. Renal Homotransplantation: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables. The effect of IMURAN on these variables has not been tested in controlled trials. Rheumatoid Arthritis: IMURAN is indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms. Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with IMURAN. The combined use of IMURAN with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of IMURAN with these agents cannot be recommended. CONTRAINDICATIONS: IMURAN should not be given to patients who have shown hypersensitivity to the drug. IMURAN should not be used for treating rheumatoid arthritis in pregnant women. Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of malignancy if treated with IMURAN. WARNINGS: Malignancy Patients receiving immunosuppressants, including IMURAN, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with IMURAN. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Post-transplant Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs, including IMURAN. Therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. 3 Reference ID: 2951014 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IMURAN ® (azathioprine) Rheumatoid Arthritis Information is available on the risk of malignancy with the use of IMURAN in rheumatoid arthritis (see ADVERSE REACTIONS). It has not been possible to define the precise risk of malignancy due to IMURAN. The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients. However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received IMURAN. Inflammatory Bowel Disease Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with IMURAN. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Some of the patients were treated with IMURAN as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis. The safety and efficacy of IMURAN for the treatment of Crohn's disease and ulcerative colitis have not been established. Cytopenias Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with IMURAN. Severe bone marrow suppression may also occur. Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing IMURAN toxicity.2-9 (See PRECAUTIONS: Laboratory Tests). Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection. It is suggested that patients on IMURAN have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count. Serious infections Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients. Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs should be considered. Effect on Sperm in Animals IMURAN has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose;10 a reduced percentage of fertile matings occurred when animals received 5 mg/kg. 11 Pregnancy: Pregnancy Category D. IMURAN can cause fetal harm when administered to a pregnant woman. IMURAN should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of IMURAN in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. 12 IMURAN is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies. 11 4 Reference ID: 2951014 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IMURAN ® (azathioprine) Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on IMURAN. In a detailed case report, 13 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily. 14 There have been two published reports of abnormal physical findings. Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy. 15 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus. The father was on long-term azathioprine therapy. 16 Benefit versus risk must be weighed carefully before use of IMURAN in patients of reproductive potential. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant. PRECAUTIONS: General: A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of therapy with IMURAN and are reversible upon discontinuation of the drug. The reaction can recur within hours after re-challenge with a single dose of IMURAN. Information for Patients: Patients being started on IMURAN should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. They should be informed of the danger of infection while receiving IMURAN and asked to report signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient, especially when IMURAN is being administered in the presence of impaired renal function or concomitantly with allopurinol (see Drug Interactions subsection and DOSAGE AND ADMINISTRATION). Patients should be advised of the potential risks of the use of IMURAN during pregnancy and during the nursing period. The increased risk of malignancy following therapy with IMURAN should be explained to the patient. Laboratory Tests: Complete Blood Count (CBC) Monitoring: Patients on IMURAN should have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. TPMT Testing: It is recommended that consideration be given to either genotype or phenotype patients for TPMT. Phenotyping and genotyping methods are commercially available. The most common non-functional alleles associated with reduced levels of TPMT activity are TPMT2, TPMT3A and TPMT3C. Patients with two non functional alleles (homozygous) have low or absent TPMT activity and those with one non-functional allele (heterozygous) have intermediate activity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. TPMT testing may also be considered in patients with abnormal CBC results that do not respond to dose reduction. Early drug discontinuation in these patients is advisable. TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections. Drug Interactions: Use with Allopurinol: One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN, to approximately 1/3 to 1/4 the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving IMURAN and allopurinol because both TPMT and XO inactivation pathways are affected. See CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS:Laboratory Tests and ADVERSE REACTIONS sections. 5 Reference ID: 2951014 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Toxicity Renal Homograft Rheumatoid Arthritis Leukopenia (any degree) >50% 28% <2500 cells/mm3 16% 5.3% Infections 20% <1% Neoplasia Lymphoma 0.5% Others 2.8% IMURAN ® (azathioprine) Use with Aminosalicylates: There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with IMURAN should be done with caution. Use with Other Agents Affecting Myelopoesis: Drugs which may affect leukocyte production, including co trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients. Use with Angiotensin-Converting Enzyme Inhibitors: The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia. Use with Warfarin: IMURAN may inhibit the anticoagulant effect of warfarin. Use with ribavirin: The use of ribavirin for hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioionosine monophosphate (6 MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary. Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section. Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section. Nursing Mothers: The use of IMURAN in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. 17, 18, 19 Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and efficacy of azathioprine in pediatric patients have not been established. ADVERSE REACTIONS: The principal and potentially serious toxic effects of IMURAN are hematologic and gastrointestinal. The risks of secondary infection and malignancy are also significant (see WARNINGS). The frequency and severity of adverse reactions depend on the dose and duration of IMURAN as well as on the patient’s underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing IMURAN for rheumatoid arthritis. The relative incidences in clinical studies are summarized below: * Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg per day) was 1.8 cases per 1000 patient-years of follow-up, compared with 0.8 cases per 1000 patient-years of follow-up in those not receiving azathioprine. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined. Hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with IMURAN. Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may 6 Reference ID: 2951014 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IMURAN ® (azathioprine) occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Anemias, including macrocytic anemia, and/or bleeding have been reported. TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for non-functional alleles) who are at increased risk for severe, life-threatening myelosuppression from IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS:Laboratory Tests. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine. 6, 20 Gastrointestinal: Nausea and vomiting may occur within the first few months of therapy with IMURAN, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of IMURAN. A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving IMURAN for panuveitis.21, 22, 23 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, IMURAN should be permanently withdrawn. Others: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, reversible interstitial pneumonitis, hepatosplenic T-cell lymphoma (see Warnings – Malignancy), and Sweet’s Syndrome (acute febrile neutrophilic dermatosis). OVERDOSAGE: The oral LD50s for single doses of IMURAN in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. About 30% of IMURAN is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis.24 A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg IMURAN. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose. DOSAGE AND ADMINISTRATION: TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity from IMURAN if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non-functional alleles). IMURAN should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction. Renal Homotransplantation: The dose of IMURAN required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. IMURAN is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of IMURAN should not be increased to toxic levels because of threatened rejection. 7 Reference ID: 2951014 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IMURAN ® (azathioprine) Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal. Rheumatoid Arthritis: IMURAN is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. IMURAN may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities. Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance IMURAN has not been determined. IMURAN can be discontinued abruptly, but delayed effects are possible. Use in Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of IMURAN or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses. Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published.25-31 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. HOW SUPPLIED: 50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with “IMURAN” and “50” on each tablet; bottle of 100 (NDC 65483-590-10). Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light. REFERENCES: 1. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43:329-339. 2. Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos. 2001;29:601-605. 3. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3:89-98. 4. Anstey A, Lennard L, Mayou SC, et al. Pancytopenia related to azathioprine – an enzyme deficiency caused by a common genetic polymorphism: a review. JR Soc Med. 1992; 85:752-756. 5. Stolk JN, Beorbooms AM, de Abreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998; 41:1858 1866. 6. Data on file, Prometheus Laboratories Inc. 7. Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997; 126:608-614. 8. Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med. 1998; 129:716-718. 9. Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology. 2004; 43:13-18. 10. Clark JM. The mutagenicity of azathioprine in mice, Drosophila melanogaster, and Neurospora crassa. Mutat Res. 1975; 28:87-99. 11. Data on file, Prometheus Laboratories Inc. 12. Tagatz GE, Simmons RL. Pregnancy after renal transplantation. Ann Intern Med. 1975; 82:113-114. Editorial Notes. 13. Cote’ CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr. 1974; 85:324-328. 8 Reference ID: 2951014 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IMURAN ® (azathioprine) 14. DeWitte DB, Buick MK, Cyran SE, et al. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. J Pediatr. 1984; 105:625-628. 15. Williamson RA, Karp LE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol. 1981; 58:247-250. 16. Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA. 1970; 211: 1854-1855. 17. Data on file, Prometheus Laboratories Inc. 18. Saarikoski S, Seppälä M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol. 1973; 115:1100-1106. 19. Coulam CB, Moyer TP, Jiang NS, et al. Breast-feeding after renal transplantation. Transplant Proc. 1982; 14: 605-609. 20. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant patients. Lancet. 1993; 341:436. 21. Read AE, Wiesner RH, LaBrecque DR, et al. Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med. 1986; 104:651-655. 22. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic veno-occlusive disease in renal transplant patients. Gastroenterology. 1986; 90:446-454. 23. Weitz H, Gokel JM, Loeshke K, et al. Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch A Pathol Anat Histol. 1982; 395:245-256. 24. Schusziarra V, Ziekursch V, Schlamp R, et al. Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol Biopharm. 1976; 14:298-302. 25. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institute of Health; 1992. US Dept of Health and Human Services. Public Health Service Publication NIH 92-2621. 26. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985; 253:1590 1592. 27. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 28. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983; 1:426-428. 29. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J for Clinicians. 1983; 33:258-263. 30. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049. 31. Yodaiken RE, Bennett D. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm, 1996; 43:1193-1204. IMURAN® and ZYLOPRIM® are registered trademarks of Prometheus Laboratories Inc. PROMETHEUS LABORATORIES INC. Manufactured by Pharmaceutics International, Inc. Hunt Valley, MD 21031 for Prometheus Laboratories Inc. San Diego, CA 92121 © Prometheus Laboratories Inc. May 2011 IM005I 9 Reference ID: 2951014 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:59.232640	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf', 'application_number': 16324, 'submission_type': 'SUPPL ', 'submission_number': 34}
10,887	5% DEXTROSE Injection, USP Trade Name® Container Rx only DESCRIPTION 5% Dextrose Injection, USP solution is sterile and nonpyrogenic. It is a parenteral solution containing dextrose in water for injection intended for intravenous administration. Each 100 mL of 5% Dextrose Injection, USP, contains dextrose, hydrous 5 g in water for injection. The caloric value is 170 kcal/L. The osmolarity is 252 mOsmol/L (calc.), which is slightly hypotonic. The solution pH is 4.3 (3.2 to 6.5). This solution contains no bacteriostat, antimicrobial agent or added buffer and is intended only as a single-dose injection. When smaller doses are required the unused portion should be discarded. 5% Dextrose Injection, USP is a parenteral fluid and nutrient replenisher. Dextrose, USP is chemically designated D-glucose monohydrate (C6H12O6 • H2O), a hexose sugar freely soluble in water. It has the following structural formula: Water for Injection, USP is chemically designated H2O. The flexible plastic container is fabricated from a clear multilayer plastic film (FC97). Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period. CLINICAL PHARMACOLOGY When administered intravenously, these solutions provide a source of water and carbohydrate. Isotonic and hypertonic concentrations of dextrose are suitable for parenteral maintenance of water requirements when salt is not needed or should be avoided. Solutions containing carbohydrate in the form of dextrose restore blood glucose levels and provide calories. Carbohydrate in the form of dextrose may aid in minimizing liver glycogen depletion and exerts a protein-sparing action. Dextrose injected parenterally undergoes oxidation to carbon dioxide and water. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirements range from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na+) plays a major role in maintaining physiologic equilibrium. RA06556 Page 1 of 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Intravenous solutions containing dextrose are indicated for parenteral replenishment of fluid and minimal carbohydrate calories as required by the clinical condition of the patient. CONTRAINDICATIONS 5% Dextrose Injection, USP without electrolytes should not be administered simultaneously with blood through the same infusion set because of the possibility that pseudoagglutination of red cells may occur. WARNINGS Excessive administration of potassium-free solutions may result in significant hypokalemia. The intravenous administration of these solutions can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of administered parenteral solutions. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of such solutions. PRECAUTIONS Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Solutions containing dextrose should be used with caution in patients with known subclinical or overt diabetes mellitus. Do not administer unless solution is clear and container is undamaged. Discard unused portion. Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic effects Pregnancy Category C. Animal reproduction studies have not been conducted with dextrose. It is also not known whether dextrose can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose should be given to a pregnant woman only if clearly needed. Nursing Mothers: Caution should be exercised when 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use: The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolarity and possible intracerebral hemorrhage. Geriatric Use: An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. RA06556 Page 2 of 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. OVERDOSAGE In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS. DOSAGE AND ADMINISTRATION The dose is dependent upon the age, weight and clinical condition of the patient. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Drug Interactions Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS. INSTRUCTIONS FOR USE Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired. If supplemental medication is desired, follow directions below before preparing for administration. To Add Medication (Use aseptic technique) 1. Remove blue cap from sterile medication additive port at bottom of container. 2. With a needle of appropriate length, puncture resealable additive port and inject. Withdraw needle after injecting medication. 3. Mix container contents thoroughly. 4. The additive port may be protected by an appropriate cover. Preparation for Administration (Use aseptic technique) NOTE: See appropriate I.V. administration set Instructions for Use. 1. Close flow control clamp of administration set. 2. Remove cap from sterile administration set port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. 4. Suspend container. 5. Squeeze and release drip chamber to establish proper fluid level in chamber. 6. Open clamp. Eliminate air from remainder of set. 7. Attach set to patient access device. 8. Begin infusion. WARNING: Do not use flexible container in series connections. RA06556 Page 3 of 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED 5% Dextrose Injection, USP is supplied in single-dose flexible plastic containers as follows: List No. Product Name Container size (mL) 7922 5% Dextrose Injection, USP 500 1000 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature.] U.S. patent 4,344,472 Revised: February 2005 ©Hospira 2005 RA06556 Printed in USA HOSPIRA INC., LAKE FOREST, IL 60045 USA RA06556 Page 4 of 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:59.253947	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/016367s178lbl.pdf', 'application_number': 16367, 'submission_type': 'SUPPL ', 'submission_number': 178}
10,888	5% Dextrose Injection, USP 25 mL TO OPEN-TEAR AT NOTCH NDC 0409-7923-20 Four Units (01) 1 030409 792320 2 Each 100 mL contains dextrose, hydrous 5 g. 252 mOsmol/liter (CALC.). pH 4.3 (3.2 to 6.5). Dextrose solutions without salts should not be used in blood transfusions because of possible rouleau formation. Single-dose container. For I.V. use. Usual Dosage: See insert. Sterile, nonpyrogenic. Use only if solution is clear. After removing the overwrap, check for minute leaks by squeezing container firmly. If leaks are found, discard solution as sterility may be impaired. Must not be used in series connections. The overwrap is a moisture barrier. Do not remove units from overwrap until ready for use. Use units promptly when pouch is opened. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. See insert. Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store. only F WR-0161 (11/05) HOSPIRA, INC., LAKE FOREST, IL 60045 USA Color PMS Black Label Control 095N, Approval Approved By Date Not Valid Unless Final Proofs Carry 095N Approval Signature White Packaging Graphics Art List Commodity CR Editor Date Artist WR-0161v4 05-6633 PP TG 7923 11/15/05 BWR 2 MIL VENDOR NOTE: White Background and Baseline to be Provided by Printing Vendor, per Drawing/ Artwork Front This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Four Units 5% Dextrose Injection, USP 25 mL B WR-0161 (11/05) Color PMS Black Label Control 095N, Approval Approved By Date Not Valid Unless Final Proofs Carry 095N Approval Signature White Packaging Graphics Art List Commodity CR Editor Date Artist WR-0161v4 05-6633 PP TG 7923 11/15/05 VENDOR NOTE: White Background to be Provided by Printing Vendor, per Drawing/ Artwork Back This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:59.289250	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/016367s182lbl.pdf', 'application_number': 16367, 'submission_type': 'SUPPL ', 'submission_number': 182}
10,891	1 Propranolol Hydrochloride Injection, USP Rx only DESCRIPTION Propranolol hydrochloride is a synthetic beta-adrenergic receptor blocking agent chemically described as (+)-1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride. Its structural formula is: s tructural formula Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80. Propranolol hydrochloride injection is available as a sterile injectable solution for intravenous administration. Each mL contains 1 mg of propranolol hydrochloride in Water for Injection. The pH is adjusted with citric acid. CLINICAL PHARMACOLOGY General Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At doses greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Mechanism of Action The effects of propranolol are due to selective blockade of beta-adrenergic receptors, leaving alpha-adrenergic responses intact. There are two well-characterized subtypes of beta receptors (beta1 and beta2); propranolol interacts with both subtypes equally. Beta1-adrenergic receptors are found primarily in the heart. Blockade of cardiac beta1-adrenergic receptors leads to a decrease in the activity of both normal and ectopic pacemaker cells and a decrease in A-V nodal conduction velocity. All of these actions can contribute to antiarrhythmic activity and control of ventricular rate during arrhythmias. Blockade of cardiac beta1-adrenergic receptors also decreases the myocardial force of contraction and may provoke cardiac decompensation in patients with minimal cardiac reserve. Beta2-adrenergic receptors are found predominantly in smooth muscle—vascular, bronchial, gastrointestinal and genitourinary. Blockade of these receptors results in constriction. Clinically, propranolol may exacerbate respiratory symptoms in patients with obstructive pulmonary diseases such as asthma and emphysema (see CONTRAINDICATIONS and WARNINGS). Propranolol’s beta blocking effects are attributable to its S(-) enantiomer. Pharmacokinetics And Drug Metabolism Distribution Propranolol has a distribution half-life (T½ alpha) of 5-10 minutes and a volume of distribution of about 4 to 5 L/kg. Approximately 90% of circulating propranolol is bound to plasma proteins. The binding is enantiomer-selective. The S-isomer is preferentially bound to alpha1 glycoprotein and the R-isomer is preferentially bound to albumin. Metabolism and Elimination The elimination half-life (T½ beta) is between 2 and 5.5 hours. Propranolol is extensively metabolized with most metabolites appearing in the urine. The major metabolites include propranolol glucuronide, naphthyloxylactic acid, and glucuronic acid and sulfate conjugates of 4- hydroxy propranolol. Following single-dose intravenous administration, side-chain oxidative products account for approximately 40% of the metabolites, direct conjugation products account for approximately 45-50% of metabolites, and ring oxidative products account for approximately 10-15% of metabolites. Of these, only the primary ring oxidative product (4- hydroxypropranolol) possesses beta-adrenergic receptor blocking activity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6. Pharmacodynamics As propranolol concentration increases, so does its beta-blocking effect, as evidenced by a reduction in exercise-induced tachycardia (n=6 normal volunteers). Special Populations Pediatric The pharmacokinetics of propranolol have not been investigated in patients under 18 years of age. Propranolol injection is not recommended for treatment of cardiac arrhythmias in pediatric patients. Geriatric Elevated propranolol plasma concentrations, a longer mean elimination half-life (254 vs. 152 minutes), and decreased systemic clearance (8 vs. 13 mL/kg/min) have been observed in elderly subjects when compared to young subjects. However, the apparent volume of distribution seems to be similar in elderly and young subjects. These findings suggest that dose adjustment of propranolol injection may be required for elderly patients (see PRECAUTIONS). Gender Intravenously administered propranolol was evaluated in 5 women and 6 men. When adjusted for weight, there were no gender-related differences in elimination half-life, volume of distribution, protein binding, or systemic clearance. Obesity In a study of intravenously administered propranolol, obese subjects had a higher AUC (161 versus 109 hr·µg/L) and lower total clearance than did non-obese subjects. Propranolol plasma protein binding was similar in both groups. Formatted This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Renal Insufficiency The pharmacokinetics of propranolol and its metabolites were evaluated in 15 subjects with varying degrees of renal function after propranolol administration via the intravenous and oral routes. When compared with normal subjects, an increase in fecal excretion of propranolol conjugates was observed in patients with increased renal impairment. Propranolol was also evaluated in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, following a single oral dose of 40 mg of propranolol. The peak plasma concentrations (Cmax) of propranolol in the chronic renal failure group were 2- to 3-fold higher (161 ng/mL) than those observed in the dialysis patients (47 ng/mL) and in the healthy subjects (26 ng/mL). Propranolol plasma clearance was also reduced in the patients with chronic renal failure. Chronic renal failure has been associated with a decrease in drug metabolism via downregulation of hepatic cytochrome P450 activity. Hepatic Insufficiency Propranolol is extensively metabolized by the liver. In a study conducted in 6 normal subjects and 20 patients with chronic liver disease, including hepatic cirrhosis, 40 mg of R-propranolol was administered intravenously. Compared to normal subjects, patients with chronic liver disease had decreased clearance of propranolol, increased volume of distribution, decreased protein-binding, and considerable variation in half-life. Caution should be exercised when propranolol is used in this population. Consideration should be given to lowering the dose of intravenous propranolol in patients with hepatic insufficiency (see PRECAUTIONS). Thyroid Dysfunction No pharmacokinetic changes were observed in hyperthyroid or hypothyroid patients when compared to their corresponding euthyroid state. Dosage adjustment does not seem necessary in either patient population based on pharmacokinetic findings. Drug Interactions Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes Because propranolol’s metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), administration of propranolol with drugs that are metabolized by, or affect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see PRECAUTIONS, Drug Interactions). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Substrates or Inhibitors of CYP2D6 Blood levels of propranolol may be increased by administration of propranolol with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavirdine, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole. Substrates or Inhibitors of CYP1A2 Blood levels of propranolol may be increased by administration of propranolol with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan. Substrates or Inhibitors of CYP2C19 Blood levels of propranolol may be increased by administration of propranolol with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, teniposide, and tolbutamide. No interaction was observed with omeprazole. Inducers of Hepatic Drug Metabolism Blood levels of propranolol may be decreased by administration of propranolol with inducers such as rifampin and ethanol. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 100% the clearance of propranolol, resulting in decreased plasma concentrations. Cardiovascular Drugs Antiarrhythmics The AUC of propafenone is increased by more than 200% with co-administration of propranolol. The metabolism of propranolol is reduced by co-administration of quinidine, leading to a 2- to 3- fold increased blood concentrations and greater beta-blockade. The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations. Calcium Channel Blockers The mean Cmax and AUC of propranolol are increased respectively, by 50% and 30% by co- administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 The mean values of Cmax and AUC of nifedipine are increased by 64% and 79%, respectively, by co-administration of propranolol. Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol. Non-Cardiovascular Drugs Migraine Drugs Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and Cmax by 37%) or rizatriptan (the AUC and Cmax were increased by 67% and 75%, respectively). Theophylline Co-administration of theophylline with propranolol decreases theophylline clearance by 33% to 52%. Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol. Neuroleptic Drugs Co-administration of propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 50% to 370% and increased thioridazine metabolites concentrations ranging from 33% to 210%. Co-administration of chlorpromazine with propranolol resulted in increased plasma levels of both drugs (70% increase in propranolol concentrations). Anti-Ulcer Drugs Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol concentrations by about 40%. Co-administration with aluminum hydroxide gel (1200 mg) resulted in a 50% decrease in propranolol concentrations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Co-administration of metoclopramide with propranolol did not have a significant effect on propranolol’s pharmacokinetics. Lipid Lowering Drugs Co-administration of cholesteramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations. Co-administration of propranolol with lovastatin or pravastatin decreased 20% to 25% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin. Warfarin Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time. CLINICAL STUDIES In a series of 225 patients with supraventricular (n=145), ventricular (n=69), or both (n=11) arrythmias resistant to digitalis, intravenous propranolol hydrochloride was administered in single doses, averaging 1 to 5 mg. Approximately one-quarter of the patients with supraventricular arrhythmias (generally those with sinus or atrial tachycardia) reverted to normal sinus rhythm. About one-half had symptoms ameliorated either by a decrease in ventricular rate or an attenuation of frequency or severity of paroxysmal attacks. Approximately one-half of patients with ventricular arrhythmias (generally those with frequent PVCs) reverted to normal sinus rhythm or responded with a reduction in ventricular rate. Similar findings were seen in a series of 25 Bantu patients with atrial fibrillation (n=16), sinus tachycardia (n=5), and multifocal ventricular extrasystoles (n=9). In another series, 7 of 8 patients with digitalis-related tachyarrhythmia had ventricular rate decreases after intravenous propranolol. Similarly limited clinical experience has shown that intravenous propranolol will slow the ventricular rate in patients with Wolff-Parkinson-White syndrome or with tachycardia associated with thyrotoxicosis. Onset of activity is usually within five minutes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 INDICATIONS AND USAGE Cardiac Arrhythmias Intravenous administration is usually reserved for life-threatening arrhythmias or those occurring under anesthesia. 1. Supraventricular arrhythmias Intravenous propranolol is indicated for the short-term treatment of supraventricular tachycardia, including Wolff-Parkinson-White syndrome and thyrotoxicosis, to decrease ventricular rate. Use in patients with atrial flutter or atrial fibrillation should be reserved for arrythmias unresponsive to standard therapy or when more prolonged control is required. Reversion to normal sinus rhythm has occasionally been observed, predominantly in patients with sinus or atrial tachycardia. 2. Ventricular tachycardias With the exception of those induced by catecholamines or digitalis, propranolol is not the drug of first choice. In critical situations when cardioversion techniques or other drugs are not indicated or are not effective, propranolol may be considered. If, after consideration of the risks involved, propranolol is used, it should be given intravenously in low dosage and very slowly, as the failing heart requires some sympathetic drive for maintenance of myocardial tone. (See DOSAGE AND ADMINISTRATION). Some patients may respond with complete reversion to normal sinus rhythm, but reduction in ventricular rate is more likely. Ventricular arrhythmias do not respond to propranolol as predictably as do the supraventricular arrhythmias. Intravenous propranolol is indicated for the treatment of persistent premature ventricular extrasystoles that impair the well-being of the patient and do not respond to conventional measures. 3. Tachyarrhythmias of digitalis intoxication Intravenous propranolol is indicated to control ventricular rate in life-threatening digitalis-induced arrhythmias. Severe bradycardia may occur. (See OVERDOSAGE). 4. Resistant tachyarrhythmias due to excessive catecholamine action during anesthesia Intravenous propranolol is indicated to abolish tachyarrhythmias due to excessive catecholamine action during anesthesia when other measures fail. These arrhythmias may arise because of release of endogenous catecholamines or administration of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 catecholamines. All general inhalation anesthetics produce some degree of myocardial depression. Therefore, when propranolol is used to treat arrhythmias during anesthesia, it should be used with extreme caution, usually with constant monitoring of the ECG and central venous pressure. (See WARNINGS). CONTRAINDICATIONS Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first-degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride. WARNINGS Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle. Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be administered with caution in this setting since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta- receptors. Major Surgery The necessity or desirability of withdrawal of beta-blocking therapy prior to major surgery is controversial. It should be noted, however, that the impaired ability of the heart to respond to reflex adrenergic stimuli in propranolol-treated patients might augment the risks of general anesthesia and surgical procedures. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin- dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting, as in preparation for surgery. Hypoglycemia has been reported after prolonged physical exertion and in patients with renal insufficiency. Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T4 and reverse T3, and decreasing T3. Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolff-Parkinson-White syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case this resulted after an initial 5 mg dose of intravenous propranolol. PRECAUTIONS General Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol is not indicated for the treatment of hypertensive emergencies. Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told that propranolol might interfere with the glaucoma screening test. Withdrawal may lead to a return of elevated intraocular pressure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Risk of anaphylactic reaction. While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks, and the patient should be cautioned against interruption or cessation of therapy without a physician’s advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it is usually advisable to reinstitute propranolol therapy and take other measures appropriate for the management of angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications. Clinical Laboratory Tests In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, serum transaminases and alkaline phosphatase. In severe heart failure, the use of propranolol has been associated with increases in Blood Urea Nitrogen. Drug Interactions Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes in its efficacy and/or toxicity (see CLINICAL PHARMACOLOGY, Drug Interactions). Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces a greater degree of clinical beta-blockade and may cause postural hypotension. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects and has been associated with severe bradycardia, asystole and heart failure when administered with propranolol. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with propranolol. The clearance of lidocaine is reduced when administered with propranolol. Lidocaine toxicity has been reported following coadministration with propranolol. Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g. digitalis, lidocaine and calcium channel blockers. Calcium Channel Blockers Caution should be exercised when patients receiving a beta-blocker are administered a calcium- channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high degree heart block, and heart failure. ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. ACE inhibitors have been reported to increase bronchial hyperreactivity when administered with propranolol. The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol should be administered cautiously to patients withdrawing from clonidine. Alpha-blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta- blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, with propranolol should be closely observed for excess reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Administration of reserpine with propranolol may also potentiate depression. Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE). Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Non-Cardiovascular Drugs Non-Steroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate. Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol. Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Warfarin Administration of propranolol with warfarin increases the concentration of warfarin. Therefore, the prothrombin time should be monitored. Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol. Thyroxine Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol. Carcinogenesis, Mutagenesis, Impairment of Fertility In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the maximum recommended human oral daily dose (MRHD) of 640 mg propranolol hydrochloride. In a study in which both male and female rats were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol hydrochloride in bacteria (S. typhimurium strain TA 1538). Pregnancy Pregnancy Category C In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation has been reported for neonates whose mothers received propranolol hydrochloride during pregnancy. Neonates whose mothers received propranolol hydrochloride at parturition have exhibited bradycardia, hypoglycemia, and respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Propranolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Propranolol is excreted in human milk. Caution should be exercised when propranolol is administered to a nursing woman. Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established. Geriatric Use Clinical studies of intravenous propranolol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly subjects have decreased clearance and a longer mean elimination half-life. These findings suggest that dose adjustment of propranolol injection may be required for elderly patients (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Hepatic Insufficiency Propranolol is extensively metabolized by the liver. Compared to normal subjects, patients with chronic liver disease have decreased clearance of propranolol, increased volume of distribution, decreased protein-binding and considerable variation in half life. Consideration should be given to lowering the dose of intravenously administered propranolol in patients with hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 ADVERSE REACTIONS In a series of 225 patients, there were 6 deaths (see CLINICAL STUDIES). Cardiovascular events (hypotension, congestive heart failure, bradycardia, and heart block) were the most common. The only other event reported by more than one patient was nausea. Other adverse events for intravenous propranolol, reported during post-marketing surveillance include cardiac arrest, dyspnea, and cutaneous ulcers. The following adverse events have been reported with use of formulations of sustained- or immediate-release oral propranolol and may be expected with intravenous propranolol. Cardiovascular Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type. Central Nervous System Light-headedness; mental depression manifested by insomnia, lassitude, weakness, fatigue; reversible mental depression progressing to catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short- term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose related. Gastrointestinal Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis. Allergic Pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory distress. Respiratory Bronchospasm. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Hematologic Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Autoimmune In extremely rare instances, systemic lupus erythematosus has been reported. Miscellaneous Alopecia, LE-like reactions, psoriaform rashes, dry eyes, male impotence, and Peyronie’s disease have been reported rarely. Oculomucocutaneous reactions involving the skin, serous membranes and conjunctivae reported for a beta-blocker (practolol) have not been associated with propranolol. OVERDOSAGE Propranolol is not significantly dialyzable. In the event of overdose or exaggerated response, the following measures should be employed: Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose. Glucagon should be administered as 50-150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine, or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be useful for bronchospasm. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The usual dose is 1 to 3 mg administered under careful monitoring, such as electrocardiography and central venous pressure. The rate of administration should not exceed 1 mg (1 mL) per minute to diminish the possibility of lowering blood pressure and causing cardiac standstill. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Sufficient time should be allowed for the drug to reach the site of action even when a slow circulation is present. If necessary, a second dose may be given after two minutes. Thereafter, additional drug should not be given in less than four hours. Additional propranolol hydrochloride should not be given when the desired alteration in rate or rhythm is achieved. Transfer to oral therapy as soon as possible. HOW SUPPLIED Each mL contains 1 mg of propranolol hydrochloride in Water for Injection. The pH is adjusted with citric acid. Supplied as: 1 mL ampuls in boxes of 10 (NDC 10019-145-01). Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing or excessive heat. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-01594/2.0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:59.603062	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/016419s029lbl.pdf', 'application_number': 16419, 'submission_type': 'SUPPL ', 'submission_number': 29}
10,890	Inderal® (propranolol hydrochloride) Tablets Rx only This product's label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-888-383-1733 DESCRIPTION Inderal® (propranolol hydrochloride) is a synthetic beta-adrenergic receptor blocking agent chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-. Its molecular and structural formulae are: structural formula Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80. Inderal is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration. The inactive ingredients contained in Inderal Tablets are: lactose, magnesium stearate, microcrystalline cellulose, and stearic acid. In addition, Inderal 10 mg and 80 mg Tablets contain FD&C Yellow No. 6 and D&C Yellow No. 10; Inderal 20 mg Tablets contain FD&C Blue No. 1; Inderal 40 mg Tablets contain FD&C Blue No. 1, FD&C Yellow No. 6, and D&C Yellow No. 10; Inderal 60 mg Tablets contain D&C Red No. 30. CLINICAL PHARMACOLOGY General Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor agonist agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain. Reference ID: 2919389 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mechanism of Action The mechanism of the antihypertensive effect of propranolol has not been established. Factors that may contribute to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use of propranolol. Effects of propranolol on plasma volume appear to be minor and somewhat variable. In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period. The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity. Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain. The mechanism of the antimigraine effect of propranolol has not been established. Beta- adrenergic receptors have been demonstrated in the pial vessels of the brain. The specific mechanism of propranolol's antitremor effects has not been established, but beta-2 (noncardiac) receptors may be involved. A central effect is also possible. Clinical studies have demonstrated that Inderal is of benefit in exaggerated physiological and essential (familial) tremor. PHARMACOKINETICS AND DRUG METABOLISM Absorption Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose. Administration of protein-rich foods increase the bioavailability of propranolol by about 50% with no change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in the urine. Distribution Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to alpha1 glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg. Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk. Reference ID: 2919389 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolism and Elimination Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41% and 17%, respectively, but with considerable variability between individuals. The four major metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol. In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6. Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range. In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance of 4-hydroxy propranolol was significantly higher and of naphthyloxyactic acid significantly lower in EMs than PMs. The plasma half-life of propranolol is from 3 to 6 hours. Enantiomers Propranolol is a racemic mixture of two enantiomers, R(+) and S(-). The S(-)-enantiomer is approximately 100 times as potent as the R(+)-enantiomer in blocking beta adrenergic receptors. In normal subjects receiving oral doses of racemic propranolol, S(-)-enantiomer concentrations exceeded those of the R(+)-enantiomer by 40-90% as a result of stereoselective hepatic metabolism. Clearance of the pharmacologically active S(-)-propranolol is lower than R(+) propranolol after intravenous and oral doses. Special Populations Geriatric In a study of 12 elderly (62-79 years old) and 12 young (25-33 years old) healthy subjects, the clearance of S(-)-enantiomer of propranolol was decreased in the elderly. Additionally, the half- life of both the R(+)- and S(-)-propranolol were prolonged in the elderly compared with the young (11 hours vs. 5 hours). Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring oxidation and side-chain oxidation). Conjugation capacity remains unchanged. In a study of 32 patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was found between age and the partial metabolic clearances to 4-hydroxypropranolol (40HP-ring oxidation) and to naphthoxylactic acid (NLA-side chain oxidation). No correlation was found between age and the partial metabolic clearance to propranolol glucuronide (PPLG-conjugation). Reference ID: 2919389 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gender In a study of 9 healthy women and 12 healthy men, neither the administration of testosterone nor the regular course of the menstrual cycle affected the plasma binding of the propranolol enantiomers. In contrast, there was a significant, although non-enantioselective diminution of the binding of propranolol after treatment with ethinyl estradiol. These findings are inconsistent with another study, in which administration of testosterone cypionate confirmed the stimulatory role of this hormone on propranolol metabolism and concluded that the clearance of propranolol in men is dependent on circulating concentrations of testosterone. In women, none of the metabolic clearances for propranolol showed any significant association with either estradiol or testosterone. Race A study conducted in 12 Caucasian and 13 African-American male subjects taking propranolol, showed that at steady state, the clearance of R(+)- and S(-)-propranolol were about 76% and 53% higher in African-Americans than in Caucasians, respectively. Chinese subjects had a greater proportion (18% to 45% higher) of unbound propranolol in plasma compared to Caucasians, which was associated with a lower plasma concentration of alpha1 acid glycoprotein. Renal Insufficiency In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma concentrations (Cmax) of propranolol in the chronic renal failure group were 2 to 3-fold higher (161±41 ng/mL) than those observed in the dialysis patients (47±9 ng/mL) and in the healthy subjects (26±1 ng/mL). Propranolol plasma clearance was also reduced in the patients with chronic renal failure. Studies have reported a delayed absorption rate and a reduced half-life of propranolol in patients with renal failure of varying severity. Despite this shorter plasma half-life, propranolol peak plasma levels were 3-4 times higher and total plasma levels of metabolites were up to 3 times higher in these patients than in subjects with normal renal function. Chronic renal failure has been associated with a decrease in drug metabolism via downregulation of hepatic cytochrome P450 activity resulting in a lower “first-pass” clearance. Propranolol is not significantly dialyzable. Hepatic Insufficiency Propranolol is extensively metabolized by the liver. In a study conducted in 7 patients with cirrhosis and 9 healthy subjects receiving 80-mg oral propranolol every 8 hours for 7 doses, the steady-state unbound propranolol concentration in patients with cirrhosis was increased 3-fold in comparison to controls. In cirrhosis, the half-life increased to 11 hours compared to 4 hours (see PRECAUTIONS). Reference ID: 2919389 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes Because propranolol's metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see Drug Interactions under PRECAUTIONS). Substrates or Inhibitors of CYP2D6 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole. Substrates or Inhibitors of CYP1A2 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan. Substrates or Inhibitors of CYP2C19 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole. Inducers of Hepatic Drug Metabolism Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations. Cardiovascular Drugs Antiarrhythmics The AUC of propafenone is increased by more than 200% by co-administration of propranolol. The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two-three fold increased blood concentration and greater degrees of clinical beta-blockade. The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations. Calcium Channel Blockers The mean Cmax and AUC of propranolol are increased, respectively, by 50% and 30% by co-administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine. The mean Cmax and AUC of nifedipine are increased by 64% and 79%, respectively, by co-administration of propranolol. Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol. Reference ID: 2919389 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Non-Cardiovascular Drugs Migraine Drugs Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and Cmax by 37%) or rizatriptan (the AUC and Cmax were increased by 67% and 75%, respectively). Theophylline Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol. Neuroleptic Drugs Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%. Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level. Anti-Ulcer Drugs Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and Cmax by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations. Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics. Lipid Lowering Drugs Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations. Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin. Warfarin Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time. Alcohol Concomitant use of alcohol may increase plasma levels of propranolol. Reference ID: 2919389 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PHARMACODYNAMICS AND CLINICAL EFFECTS Hypertension In a retrospective, uncontrolled study, 107 patients with diastolic blood pressure 110 to 150 mmHg received propranolol 120 mg t.i.d. for at least 6 months, in addition to diuretics and potassium, but with no other antihypertensive agent. Propranolol contributed to control of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure cannot be ascertained. Angina Pectoris In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years, with stable angina, propranolol 100 mg t.i.d. was administered for 4 weeks and shown to be more effective than placebo in reducing the rate of angina episodes and in prolonging total exercise time. Atrial Fibrillation In a report examining the long-term (5-22 months) efficacy of propranolol, 10 patients, aged 27 to 80, with atrial fibrillation and ventricular rate >120 beats per minute despite digitalis, received propranolol up to 30 mg t.i.d. Seven patients (70%) achieved ventricular rate reduction to <100 beats per minute. Myocardial Infarction The Beta-Blocker Heart Attack Trial (BHAT) was a National Heart, Lung and Blood Institute- sponsored multicenter, randomized, double-blind, placebo-controlled trial conducted in 31 U.S. centers (plus one in Canada) in 3,837 persons without history of severe congestive heart failure or presence of recent heart failure; certain conduction defects; angina since infarction, who had survived the acute phase of myocardial infarction. Propranolol was administered at either 60 or 80 mg t.i.d. based on blood levels achieved during an initial trial of 40 mg t.i.d. Therapy with Inderal, begun 5 to 21 days following infarction, was shown to reduce overall mortality up to 39 months, the longest period of follow-up. This was primarily attributable to a reduction in cardiovascular mortality. The protective effect of Inderal was consistent regardless of age, sex, or site of infarction. Compared with placebo, total mortality was reduced 39% at 12 months and 26% over an average follow-up period of 25 months. The Norwegian Multicenter Trial in which propranolol was administered at 40 mg q.i.d. gave overall results which support the findings in the BHAT. Although the clinical trials used either t.i.d. or q.i.d. dosing, clinical, pharmacologic, and pharmacokinetic data provide a reasonable basis for concluding that b.i.d. dosing with propranolol should be adequate in the treatment of postinfarction patients. Migraine In a 34-week, placebo-controlled, 4-period, dose-finding crossover study with a double-blind randomized treatment sequence, 62 patients with migraine received propranolol 20 to 80 mg 3 or 4 times daily. The headache unit index, a composite of the number of days with headache and the associated severity of the headache, was significantly reduced for patients receiving propranolol as compared to those on placebo. Reference ID: 2919389 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Essential Tremor In a 2 week, double-blind, parallel, placebo-controlled study of 9 patients with essential or familial tremor, propranolol, at a dose titrated as needed from 40-80 mg t.i.d. reduced tremor severity compared to placebo. Hypertrophic Subaortic Stenosis In an uncontrolled series of 13 patients with New York Heart Association (NYHA) class 2 or 3 symptoms and hypertrophic subaortic stenosis diagnosed at cardiac catheterization, oral propranolol 40-80 mg t.i.d. was administered and patients were followed for up to 17 months. Propranolol was associated with improved NYHA class for most patients. Pheochromocytoma In an uncontrolled series of 3 patients with norepinephrine-secreting pheochromocytoma who were pretreated with an alpha adrenergic blocker (prazosin), perioperative use of propranolol at doses of 40-80 mg t.i.d. resulted in symptomatic blood pressure control. INDICATIONS AND USAGE Hypertension Inderal is indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Inderal is not indicated in the management of hypertensive emergencies. Angina Pectoris Due to Coronary Atherosclerosis Inderal is indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris. Atrial Fibrillation Inderal is indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response. Myocardial Infarction Inderal is indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable. Migraine Inderal is indicated for the prophylaxis of common migraine headache. The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use. Essential Tremor Inderal is indicated in the management of familial or hereditary essential tremor. Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs. It is absent at rest, but occurs when the limb is held in a fixed posture or position against gravity and during active movement. Inderal causes a reduction in the tremor amplitude, but not in the tremor frequency. Inderal is not indicated for the treatment of tremor associated with Parkinsonism. Reference ID: 2919389 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypertrophic Subaortic Stenosis Inderal improves NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis. Pheochromocytoma Inderal is indicated as an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine-secreting tumors. CONTRAINDICATIONS Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride. WARNINGS Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks and the patient should be cautioned against interruption or cessation of therapy without the physician's advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications. Hypersensitivity and Skin Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ADVERSE REACTIONS). Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS). Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle. In Patients without a History of Heart Failure, continued use of beta blockers can, in some cases, lead to cardiac failure. Reference ID: 2919389 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors. Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin- dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia, especially during fasting as in preparation for surgery. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency. Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T4 and reverse T3 and decreasing T3. Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this result was reported after an initial dose of 5 mg propranolol. Pheochromocytoma Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) action unopposed. In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure. PRECAUTIONS General Propranolol should be used with caution in patients with impaired hepatic or renal function. Inderal is not indicated for the treatment of hypertensive emergencies. Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told that Inderal may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure. Reference ID: 2919389 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. Clinical Laboratory Tests In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, serum transaminases and alkaline phosphatase. In severe heart failure, the use of propranolol has been associated with increases in Blood Urea Nitrogen. Drug Interactions Caution should be exercised when Inderal is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG METABOLISM). Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol. The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following coadministration with propranolol. Caution should be exercised when administering Inderal with drugs that slow A-V nodal conduction, e.g. digitalis, lidocaine and calcium channel blockers. Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium- channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure. Reference ID: 2919389 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. The antihypertensive effects of clonidine may be antagonized by beta-blockers. Inderal should be administered cautiously to patients withdrawing from clonidine. Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta- blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin. Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE). Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Non-Cardiovascular Drugs Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate. Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol. Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol. Reference ID: 2919389 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Warfarin Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored. Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol. Thyroxine Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol. Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol. Carcinogenesis, Mutagenesis, Impairment of Fertility In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the maximum recommended human oral daily dose (MRHD) of 640 mg propranolol hydrochloride. In a study in which both male and female rats were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol hydrochloride in bacteria (S. typhimurium strain TA 1538). Pregnancy: Pregnancy Category C In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted. There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Inderal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Propranolol is excreted in human milk. Caution should be exercised when Inderal is administered to a nursing woman. Reference ID: 2919389 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established. Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients. Geriatric Use Clinical studies of Inderal did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS The following adverse events were observed and have been reported in patients using propranolol. Cardiovascular: Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type. Central Nervous System: Light-headedness, mental depression manifested by insomnia, lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose-related. Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis. Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory distress. Respiratory: Bronchospasm. Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Autoimmune: Systemic lupus erythematosus (SLE). Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes and conjunctivae reported for a beta blocker (practolol) have not been associated with propranolol. Genitourinary: Male impotence; Peyronie's disease. Reference ID: 2919389 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the following measures should be employed: General: If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary aspiration. Supportive Therapy: Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose. Glucagon should be administered as 50 150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm. DOSAGE AND ADMINISTRATION General Because of the variable bioavailability of propranolol, the dose should be individualized based on response. Hypertension The usual initial dosage is 40 mg Inderal twice daily, whether used alone or added to a diuretic. Dosage may be increased gradually until adequate blood pressure control is achieved. The usual maintenance dosage is 120 mg to 240 mg per day. In some instances a dosage of 640 mg a day may be required. The time needed for full antihypertensive response to a given dosage is variable and may range from a few days to several weeks. While twice-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, some patients, especially when lower doses are used, may experience a modest rise in blood pressure toward the end of the 12-hour dosing interval. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. If control is not adequate, a larger dose, or 3-times-daily therapy may achieve better control. Angina Pectoris Total daily doses of 80 mg to 320 mg Inderal, when administered orally, twice a day, three times a day, or four times a day, have been shown to increase exercise tolerance and to reduce ischemic changes in the ECG. If treatment is to be discontinued, reduce dosage gradually over a period of several weeks. (See WARNINGS.) Atrial Fibrillation The recommended dose is 10 mg to 30 mg Inderal three or four times daily before meals and at bedtime. Reference ID: 2919389 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Myocardial Infarction In the Beta-Blocker Heart Attack Trial (BHAT), the initial dose was 40 mg t.i.d., with titration after 1 month to 60 mg to 80 mg t.i.d. as tolerated. The recommended daily dosage is 180 mg to 240 mg Inderal per day in divided doses. Although a t.i.d. regimen was used in the BHAT and a q.i.d. regimen in the Norwegian Multicenter Trial, there is a reasonable basis for the use of either a t.i.d. or b.i.d. regimen (see PHARMACODYNAMICS AND CLINICAL EFFECTS). The effectiveness and safety of daily dosages greater than 240 mg for prevention of cardiac mortality have not been established. However, higher dosages may be needed to effectively treat coexisting diseases such as angina or hypertension (see above). Migraine The initial dose is 80 mg Inderal daily in divided doses. The usual effective dose range is 160 mg to 240 mg per day. The dosage may be increased gradually to achieve optimum migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximum dose, Inderal therapy should be discontinued. It may be advisable to withdraw the drug gradually over a period of several weeks. Essential Tremor The initial dosage is 40 mg Inderal twice daily. Optimum reduction of essential tremor is usually achieved with a dose of 120 mg per day. Occasionally, it may be necessary to administer 240 mg to 320 mg per day. Hypertrophic Subaortic Stenosis The usual dosage is 20 mg to 40 mg Inderal three or four times daily before meals and at bedtime. Pheochromocytoma The usual dosage is 60 mg Inderal daily in divided doses for three days prior to surgery as adjunctive therapy to alpha-adrenergic blockade. For the management of inoperable tumors, the usual dosage is 30 mg daily in divided doses as adjunctive therapy to alpha-adrenergic blockade. HOW SUPPLIED Inderal® (propranolol hydrochloride) Tablets INDERAL 10—Each hexagonal-shaped, orange, scored tablet, embossed with an “I” and imprinted with “INDERAL 10,” contains 10 mg propranolol hydrochloride, in bottles of 100 (NDC 24090) and 5,000 (NDC 24090-421-88). Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). Dispense in a well-closed container as defined in the USP. INDERAL 20—Each hexagonal-shaped, blue, scored tablet, embossed with an “I” and imprinted with “INDERAL 20,” contains 20 mg propranolol hydrochloride, in bottles of 100 (NDC 24090-422-88). Reference ID: 2919389 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c o mpany logo Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). Dispense in a well-closed, light-resistant container as defined in the USP. Protect from light. Use carton to protect contents from light. INDERAL 40—Each hexagonal-shaped, green, scored tablet, embossed with an “I” and imprinted with “INDERAL 40,” contains 40 mg propranolol hydrochloride, in bottles of 100 (NDC 24090) and 5,000 (NDC 24090-424-88). Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). Dispense in a well-closed, light-resistant container as defined in the USP. Protect from light. Use carton to protect contents from light. INDERAL 60—Each hexagonal-shaped, pink, scored tablet, embossed with an “I” and imprinted with “INDERAL 60,” contains 60 mg propranolol hydrochloride, in bottles of 100 (NDC 24090-426-88). Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). Dispense in a well-closed container as defined in the USP. INDERAL 80—Each hexagonal-shaped, yellow, scored tablet, embossed with an “I” and imprinted with “INDERAL 80,” contains 80 mg propranolol hydrochloride, in bottles of 100 (NDC 24090-428-88). Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature] Dispense in a well-closed container as defined in the USP. The appearance of these tablets is a registered trademark of Wyeth Pharmaceuticals. Manufactured for Akrimax Pharmaceuticals, LLC Cranford, NJ 07016 Reference ID: 2919389 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda By Wyeth Pharmaceuticals, Inc. Philadelphia, PA 19101 Marketed and Distributed by Akrimax Pharmaceuticals, LLC Cranford, NJ 07016 542F100 Rev 11/10 Reference ID: 2919389 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:59.771912	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016418s080,016762s017,017683s008lbl.pdf', 'application_number': 16418, 'submission_type': 'SUPPL ', 'submission_number': 80}
10,889	Inderal® (propranolol hydrochloride) Tablets Rx only This product's label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. DESCRIPTION Inderal® (propranolol hydrochloride) is a synthetic beta-adrenergic receptor blocking agent chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-. Its molecular and structural formulae are: Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80. Inderal is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration. The inactive ingredients contained in Inderal Tablets are: lactose, magnesium stearate, microcrystalline cellulose, and stearic acid. In addition, Inderal 10 mg and 80 mg Tablets contain FD&C Yellow No. 6 and D&C Yellow No. 10; Inderal 20 mg Tablets contain FD&C Blue No. 1; Inderal 40 mg Tablets contain FD&C Blue No. 1, FD&C Yellow No. 6, and D&C Yellow No. 10; Inderal 60 mg Tablets contain D&C Red No. 30. CLINICAL PHARMACOLOGY General Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor agonist agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mechanism of Action The mechanism of the antihypertensive effect of propranolol has not been established. Factors that may contribute to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use of propranolol. Effects of propranolol on plasma volume appear to be minor and somewhat variable. In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period. The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity. Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain. The mechanism of the antimigraine effect of propranolol has not been established. Beta- adrenergic receptors have been demonstrated in the pial vessels of the brain. The specific mechanism of propranolol's antitremor effects has not been established, but beta-2 (noncardiac) receptors may be involved. A central effect is also possible. Clinical studies have demonstrated that Inderal is of benefit in exaggerated physiological and essential (familial) tremor. PHARMACOKINETICS AND DRUG METABOLISM Absorption Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose. Administration of protein-rich foods increase the bioavailability of propranolol by about 50% with no change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in the urine. Distribution Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to alpha1 glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg. Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolism and Elimination Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41% and 17%, respectively, but with considerable variability between individuals. The four major metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol. In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6. Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range. In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance of 4-hydroxy propranolol was significantly higher and of naphthyloxyactic acid significantly lower in EMs than PMs. The plasma half-life of propranolol is from 3 to 6 hours. Enantiomers Propranolol is a racemic mixture of two enantiomers, R(+) and S(-). The S(-)-enantiomer is approximately 100 times as potent as the R(+)-enantiomer in blocking beta adrenergic receptors. In normal subjects receiving oral doses of racemic propranolol, S(-)-enantiomer concentrations exceeded those of the R(+)-enantiomer by 40-90% as a result of stereoselective hepatic metabolism. Clearance of the pharmacologically active S(-)-propranolol is lower than R(+)- propranolol after intravenous and oral doses. Special Populations Geriatric In a study of 12 elderly (62-79 years old) and 12 young (25-33 years old) healthy subjects, the clearance of S(-)-enantiomer of propranolol was decreased in the elderly. Additionally, the half- life of both the R(+)- and S(-)-propranolol were prolonged in the elderly compared with the young (11 hours vs. 5 hours). Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring oxidation and side-chain oxidation). Conjugation capacity remains unchanged. In a study of 32 patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was found between age and the partial metabolic clearances to 4-hydroxypropranolol (40HP-ring oxidation) and to naphthoxylactic acid (NLA-side chain oxidation). No correlation was found between age and the partial metabolic clearance to propranolol glucuronide (PPLG-conjugation). 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gender In a study of 9 healthy women and 12 healthy men, neither the administration of testosterone nor the regular course of the menstrual cycle affected the plasma binding of the propranolol enantiomers. In contrast, there was a significant, although non-enantioselective diminution of the binding of propranolol after treatment with ethinyl estradiol. These findings are inconsistent with another study, in which administration of testosterone cypionate confirmed the stimulatory role of this hormone on propranolol metabolism and concluded that the clearance of propranolol in men is dependent on circulating concentrations of testosterone. In women, none of the metabolic clearances for propranolol showed any significant association with either estradiol or testosterone. Race A study conducted in 12 Caucasian and 13 African-American male subjects taking propranolol, showed that at steady state, the clearance of R(+)- and S(-)-propranolol were about 76% and 53% higher in African-Americans than in Caucasians, respectively. Chinese subjects had a greater proportion (18% to 45% higher) of unbound propranolol in plasma compared to Caucasians, which was associated with a lower plasma concentration of alpha1 acid glycoprotein. Renal Insufficiency In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma concentrations (Cmax) of propranolol in the chronic renal failure group were 2 to 3-fold higher (161±41 ng/mL) than those observed in the dialysis patients (47±9 ng/mL) and in the healthy subjects (26±1 ng/mL). Propranolol plasma clearance was also reduced in the patients with chronic renal failure. Studies have reported a delayed absorption rate and a reduced half-life of propranolol in patients with renal failure of varying severity. Despite this shorter plasma half-life, propranolol peak plasma levels were 3-4 times higher and total plasma levels of metabolites were up to 3 times higher in these patients than in subjects with normal renal function. Chronic renal failure has been associated with a decrease in drug metabolism via downregulation of hepatic cytochrome P450 activity resulting in a lower “first-pass” clearance. Hepatic Insufficiency Propranolol is extensively metabolized by the liver. In a study conducted in 7 patients with cirrhosis and 9 healthy subjects receiving 80-mg oral propranolol every 8 hours for 7 doses, the steady-state unbound propranolol concentration in patients with cirrhosis was increased 3-fold in comparison to controls. In cirrhosis, the half-life increased to 11 hours compared to 4 hours (see PRECAUTIONS). 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes Because propranolol's metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see Drug Interactions under PRECAUTIONS). Substrates or Inhibitors of CYP2D6 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole. Substrates or Inhibitors of CYP1A2 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan. Substrates or Inhibitors of CYP2C19 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole. Inducers of Hepatic Drug Metabolism Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations. Cardiovascular Drugs Antiarrhythmics The AUC of propafenone is increased by more than 200% by co-administration of propranolol. The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two-three fold increased blood concentration and greater degrees of clinical beta-blockade. The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations. Calcium Channel Blockers The mean Cmax and AUC of propranolol are increased, respectively, by 50% and 30% by co-administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine. The mean Cmax and AUC of nifedipine are increased by 64% and 79%, respectively, by co-administration of propranolol. Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Non-Cardiovascular Drugs Migraine Drugs Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and Cmax by 37%) or rizatriptan (the AUC and Cmax were increased by 67% and 75%, respectively). Theophylline Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol. Neuroleptic Drugs Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%. Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level. Anti-Ulcer Drugs Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and Cmax by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations. Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics. Lipid Lowering Drugs Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations. Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin. Warfarin Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time. Alcohol Concomitant use of alcohol may increase plasma levels of propranolol. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PHARMACODYNAMICS AND CLINICAL EFFECTS Hypertension In a retrospective, uncontrolled study, 107 patients with diastolic blood pressure 110 to 150 mmHg received propranolol 120 mg t.i.d. for at least 6 months, in addition to diuretics and potassium, but with no other antihypertensive agent. Propranolol contributed to control of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure cannot be ascertained. Angina Pectoris In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years, with stable angina, propranolol 100 mg t.i.d. was administered for 4 weeks and shown to be more effective than placebo in reducing the rate of angina episodes and in prolonging total exercise time. Atrial Fibrillation In a report examining the long-term (5-22 months) efficacy of propranolol, 10 patients, aged 27 to 80, with atrial fibrillation and ventricular rate >120 beats per minute despite digitalis, received propranolol up to 30 mg t.i.d. Seven patients (70%) achieved ventricular rate reduction to <100 beats per minute. Myocardial Infarction The Beta-Blocker Heart Attack Trial (BHAT) was a National Heart, Lung and Blood Institute- sponsored multicenter, randomized, double-blind, placebo-controlled trial conducted in 31 U.S. centers (plus one in Canada) in 3,837 persons without history of severe congestive heart failure or presence of recent heart failure; certain conduction defects; angina since infarction, who had survived the acute phase of myocardial infarction. Propranolol was administered at either 60 or 80 mg t.i.d. based on blood levels achieved during an initial trial of 40 mg t.i.d. Therapy with Inderal, begun 5 to 21 days following infarction, was shown to reduce overall mortality up to 39 months, the longest period of follow-up. This was primarily attributable to a reduction in cardiovascular mortality. The protective effect of Inderal was consistent regardless of age, sex, or site of infarction. Compared with placebo, total mortality was reduced 39% at 12 months and 26% over an average follow-up period of 25 months. The Norwegian Multicenter Trial in which propranolol was administered at 40 mg q.i.d. gave overall results which support the findings in the BHAT. Although the clinical trials used either t.i.d. or q.i.d. dosing, clinical, pharmacologic, and pharmacokinetic data provide a reasonable basis for concluding that b.i.d. dosing with propranolol should be adequate in the treatment of postinfarction patients. Migraine In a 34-week, placebo-controlled, 4-period, dose-finding crossover study with a double-blind randomized treatment sequence, 62 patients with migraine received propranolol 20 to 80 mg 3 or 4 times daily. The headache unit index, a composite of the number of days with headache and the associated severity of the headache, was significantly reduced for patients receiving propranolol as compared to those on placebo. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Essential Tremor In a 2 week, double-blind, parallel, placebo-controlled study of 9 patients with essential or familial tremor, propranolol, at a dose titrated as needed from 40-80 mg t.i.d. reduced tremor severity compared to placebo. Hypertrophic Subaortic Stenosis In an uncontrolled series of 13 patients with New York Heart Association (NYHA) class 2 or 3 symptoms and hypertrophic subaortic stenosis diagnosed at cardiac catheterization, oral propranolol 40-80 mg t.i.d. was administered and patients were followed for up to 17 months. Propranolol was associated with improved NYHA class for most patients. Pheochromocytoma In an uncontrolled series of 3 patients with norepinephrine-secreting pheochromocytoma who were pretreated with an alpha adrenergic blocker (prazosin), perioperative use of propranolol at doses of 40-80 mg t.i.d. resulted in symptomatic blood pressure control. INDICATIONS AND USAGE Hypertension Inderal is indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Inderal is not indicated in the management of hypertensive emergencies. Angina Pectoris Due to Coronary Atherosclerosis Inderal is indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris. Atrial Fibrillation Inderal is indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response. Myocardial Infarction Inderal is indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable. Migraine Inderal is indicated for the prophylaxis of common migraine headache. The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use. Essential Tremor Inderal is indicated in the management of familial or hereditary essential tremor. Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs. It is absent at rest, but occurs when the limb is held in a fixed posture or position against gravity and during active movement. Inderal causes a reduction in the tremor amplitude, but not in the tremor frequency. Inderal is not indicated for the treatment of tremor associated with Parkinsonism. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypertrophic Subaortic Stenosis Inderal improves NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis. Pheochromocytoma Inderal is indicated as an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine-secreting tumors. CONTRAINDICATIONS Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride. WARNINGS Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks and the patient should be cautioned against interruption or cessation of therapy without the physician's advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications. Hypersensitivity and Skin Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ADVERSE REACTIONS). Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS). Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle. In Patients without a History of Heart Failure, continued use of beta blockers can, in some cases, lead to cardiac failure. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors. Major Surgery The necessity or desirability of withdrawal of beta-blocking therapy prior to major surgery is controversial. It should be noted, however, that the impaired ability of the heart to respond to reflex adrenergic stimuli in propranolol-treated patients may augment the risks of general anesthesia and surgical procedures. Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin- dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia, especially during fasting as in preparation for surgery. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency. Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T4 and reverse T3 and decreasing T3. Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this result was reported after an initial dose of 5 mg propranolol. Pheochromocytoma Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) action unopposed. In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Propranolol should be used with caution in patients with impaired hepatic or renal function. Inderal is not indicated for the treatment of hypertensive emergencies. Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told that Inderal may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure. While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. Clinical Laboratory Tests In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, serum transaminases and alkaline phosphatase. In severe heart failure, the use of propranolol has been associated with increases in Blood Urea Nitrogen. Drug Interactions Caution should be exercised when Inderal is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG METABOLISM). Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension. Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects and has been associated with severe bradycardia, asystole and heart failure when administered with propranolol. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with propranolol. The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following coadministration with propranolol. Caution should be exercised when administering Inderal with drugs that slow A-V nodal conduction, e.g. lidocaine and calcium channel blockers. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium- channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure. ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. Certain ACE inhibitors have been reported to increase bronchial hyperreactivity when administered with propranolol. The antihypertensive effects of clonidine may be antagonized by beta-blockers. Inderal should be administered cautiously to patients withdrawing from clonidine. Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta- blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin. Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Administration of reserpine with propranolol may also potentiate depression. Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE). 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Non-Cardiovascular Drugs Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate. Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol. Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol. Warfarin Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored. Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol. Thyroxine Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol. Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol. Carcinogenesis, Mutagenesis, Impairment of Fertility In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the maximum recommended human oral daily dose (MRHD) of 640 mg propranolol hydrochloride. In a study in which both male and female rats were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol hydrochloride in bacteria (S. typhimurium strain TA 1538). 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Pregnancy Category C In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted. There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Inderal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Propranolol is excreted in human milk. Caution should be exercised when Inderal is administered to a nursing woman. Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established. Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients. Geriatric Use Clinical studies of Inderal did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS The following adverse events were observed and have been reported in patients using propranolol. Cardiovascular: Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type. Central Nervous System: Light-headedness, mental depression manifested by insomnia, lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda neuropsychometrics. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose-related. Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis. Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory distress. Respiratory: Bronchospasm. Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Autoimmune: Systemic lupus erythematosus (SLE). Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes and conjunctivae reported for a beta blocker (practolol) have not been associated with propranolol. Genitourinary: Male impotence; Peyronie's disease. OVERDOSAGE Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the following measures should be employed: General: If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary aspiration. Supportive Therapy: Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose. Glucagon should be administered as 50- 150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm. DOSAGE AND ADMINISTRATION General Because of the variable bioavailability of propranolol, the dose should be individualized based on response. 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypertension The usual initial dosage is 40 mg Inderal twice daily, whether used alone or added to a diuretic. Dosage may be increased gradually until adequate blood pressure control is achieved. The usual maintenance dosage is 120 mg to 240 mg per day. In some instances a dosage of 640 mg a day may be required. The time needed for full antihypertensive response to a given dosage is variable and may range from a few days to several weeks. While twice-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, some patients, especially when lower doses are used, may experience a modest rise in blood pressure toward the end of the 12-hour dosing interval. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. If control is not adequate, a larger dose, or 3-times-daily therapy may achieve better control. Angina Pectoris Total daily doses of 80 mg to 320 mg Inderal, when administered orally, twice a day, three times a day, or four times a day, have been shown to increase exercise tolerance and to reduce ischemic changes in the ECG. If treatment is to be discontinued, reduce dosage gradually over a period of several weeks. (See WARNINGS.) Atrial Fibrillation The recommended dose is 10 mg to 30 mg Inderal three or four times daily before meals and at bedtime. Myocardial Infarction In the Beta-Blocker Heart Attack Trial (BHAT), the initial dose was 40 mg t.i.d., with titration after 1 month to 60 mg to 80 mg t.i.d. as tolerated. The recommended daily dosage is 180 mg to 240 mg Inderal per day in divided doses. Although a t.i.d. regimen was used in the BHAT and a q.i.d. regimen in the Norwegian Multicenter Trial, there is a reasonable basis for the use of either a t.i.d. or b.i.d. regimen (see PHARMACODYNAMICS AND CLINICAL EFFECTS). The effectiveness and safety of daily dosages greater than 240 mg for prevention of cardiac mortality have not been established. However, higher dosages may be needed to effectively treat coexisting diseases such as angina or hypertension (see above). Migraine The initial dose is 80 mg Inderal daily in divided doses. The usual effective dose range is 160 mg to 240 mg per day. The dosage may be increased gradually to achieve optimum migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximum dose, Inderal therapy should be discontinued. It may be advisable to withdraw the drug gradually over a period of several weeks. Essential Tremor The initial dosage is 40 mg Inderal twice daily. Optimum reduction of essential tremor is usually achieved with a dose of 120 mg per day. Occasionally, it may be necessary to administer 240 mg to 320 mg per day. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypertrophic Subaortic Stenosis The usual dosage is 20 mg to 40 mg Inderal three or four times daily before meals and at bedtime. Pheochromocytoma The usual dosage is 60 mg Inderal daily in divided doses for three days prior to surgery as adjunctive therapy to alpha-adrenergic blockade. For the management of inoperable tumors, the usual dosage is 30 mg daily in divided doses as adjunctive therapy to alpha-adrenergic blockade. HOW SUPPLIED Inderal® (propranolol hydrochloride) Tablets INDERAL 10—Each hexagonal-shaped, orange, scored tablet, embossed with an “I” and imprinted with “INDERAL 10,” contains 10 mg propranolol hydrochloride, in bottles of 100 (NDC 0046-0421-81) and 5,000 (NDC 0046-0421-95). Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). Dispense in a well-closed container as defined in the USP. INDERAL 20—Each hexagonal-shaped, blue, scored tablet, embossed with an “I” and imprinted with “INDERAL 20,” contains 20 mg propranolol hydrochloride, in bottles of 100 (NDC 0046-0422-81). Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). Dispense in a well-closed, light-resistant container as defined in the USP. Protect from light. Use carton to protect contents from light. INDERAL 40—Each hexagonal-shaped, green, scored tablet, embossed with an “I” and imprinted with “INDERAL 40,” contains 40 mg propranolol hydrochloride, in bottles of 100 (NDC 0046-0424-81) and 5,000 (NDC 0046-0424-95). Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). Dispense in a well-closed, light-resistant container as defined in the USP. Protect from light. Use carton to protect contents from light. 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDERAL 60—Each hexagonal-shaped, pink, scored tablet, embossed with an “I” and imprinted with “INDERAL 60,” contains 60 mg propranolol hydrochloride, in bottles of 100 (NDC 0046-0426-81). Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). Dispense in a well-closed container as defined in the USP. INDERAL 80—Each hexagonal-shaped, yellow, scored tablet, embossed with an “I” and imprinted with “INDERAL 80,” contains 80 mg propranolol hydrochloride, in bottles of 100 (NDC 0046-0428-81). Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature] Dispense in a well-closed container as defined in the USP. The appearance of these tablets is a registered trademark of Wyeth Pharmaceuticals. Wyeth® Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 (Update W10486C005) (Update ET01) (Update Rev Date) 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:59.852429	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016418s078lbl.pdf', 'application_number': 16418, 'submission_type': 'SUPPL ', 'submission_number': 78}
10,892	NDA 16-466/S-040 NDA 16-466/S-041 Page 3 Aristospan® (Triamcinolone Hexacetonide Injectable Suspension, USP) 5 mg/mL PARENTERAL NOT FOR USE IN NEWBORNS FOR INTRALESIONAL ADMINISTRATION NOT FOR INTRAVENOUS USE DESCRIPTION A sterile suspension containing 5 mg/mL of micronized triamcinolone hexacetonide in the following inactive ingredients: Polysorbate 80 0.20% w/v Sorbitol Solution USP 50.00% w/v Water for Injection qs ad 100.00% V Hydrochloric Acid and Sodium Hydroxide, if required, to adjust pH to 4.0-8.0 Preservative: Benzyl Alcohol 0.90% w/v Chemically triamcinolone hexacetonide USP is 9α-Fluoro-11β,16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone 21-(3,3-dimethylbutyrate). The molecular weight is 532.65. The structural formula is: Structural Formula This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 4 The hexacetonide ester of the glucocorticoid triamcinolone is relatively insoluble (0.0002% at 25°C in water). CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders of many organ systems. When injected intralesionally or sublesionally, triamcinolone hexacetonide can be expected to be absorbed slowly from the injection site. INDICATIONS AND USAGE The intralesional administration of Aristospan (triamcinolone hexacetonide injectable suspension, USP) 5 mg/mL is indicated for alopecia areata; discoid lupus erythematosus; keloids; localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; necrobiosis lipoidica diabeticorum. Aristospan may also be useful in cystic tumors of an aponeurosis or tendon (ganglia). CONTRAINDICATIONS Aristospan is contraindicated in patients who are hypersensitive to any components of this product. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. WARNINGS General This product contains benzyl alcohol. Benzyl alcohol has been associated with a fatal “Gasping Syndrome” in premature infants and infants of low birth weight. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS: Pediatric Use). Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Results from one multicenter, randomized, placebo controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 5 trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of corticosteroids, including Aristospan®, should not be used for the treatment of traumatic brain injury. Cardio-renal Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Infections General Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS: Drug Interactions: Amphotericin B Injection and Potassium-Depleting Agents). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Corticosteroids should not be used in cerebral malaria. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 6 Tuberculosis If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccination Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease. Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered. Neurologic Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS: Gastrointestinal and Neurologic/Psychiatric). Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction must be gradual. Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Atrophy at the site of injection has been reported. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 7 Cardio-renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy. Injection of a steroid into an infected site is to be avoided. Neuro-psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect (see DOSAGE AND ADMINISTRATION). An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 8 Information for Patients Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions Aminoglutethimide Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B Injection and Potassium-Depleting Agents When corticosteroids are administered concomitantly with potassium-depleting agents (i. e., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, Oral Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular Drugs Serum concentrations of isoniazid may be decreased. Cholestyramine Cholestyramine may increase the clearance of corticosteroids. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 9 Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis Glycosides Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including Oral Contraceptives Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin) Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 10 Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal Anti-Inflammatory Agents (NSAIDs) Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin Tests Corticosteroids may suppress reactions to skin tests. Vaccines Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections: Vaccination). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 11 Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman. Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low- birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 12 Geriatric Use No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS (listed alphabetically, under each subsection) Allergic Reactions Anaphylactoid reactions, anaphylaxis, angioedema. Cardiovascular Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetics, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and Electrolyte Disturbances Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 13 Negative nitrogen balance due to protein catabolism. Musculoskeletal Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot- like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS: Infections: Neurologic). Ophthalmic Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS) General The initial dosage of Aristospan (triamcinolone hexacetonide injectable suspension, USP) may vary from 2 to 48 mg per day depending on the specific disease entity being treated. However, in certain overwhelming, acute, life- threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. It Should Be Emphasized That Dosage Requirements Are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long- term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 14 In pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in three or four divided doses (3.2 to 48 mg/m2bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. Directions for Use Strict aseptic administration technique is mandatory. Topical ethylchloride spray may be used locally before injection. The syringe should be gently agitated to achieve uniform suspension before use. Since this product has been designed for ease of administration, a small bore needle (not smaller than 23 gauge) may be used. Dilution Aristospan suspension may also be mixed with 1% or 2% Lidocaine Hydrochloride, using the formulations which do not contain parabens. Similar local anesthetics may also be used. Diluents containing methylparaben, propylparaben, phenol, etc. should be avoided since these compounds may cause flocculation of the steroid. These dilutions will retain full potency for one week, but care should be exercised to avoid contamination of the vial’s contents and the dilutions should be discarded after 7 days. Aristospan suspension 5 mg/mL may also be diluted, if desired, with Dextrose and Sodium Chloride Injection USP, (5% and 10% Dextrose), Sodium Chloride Injection USP, or Sterile Water for Injection USP. The optimum dilution, i.e., 1:1, 1:2, 1:4, should be determined by the nature of the lesion, its size, the depth of injection, the volume needed, and location of the lesion. In general, more superficial injections should be performed with greater dilution. Certain conditions, such as keloids, require a less dilute suspension such as 5 mg/mL, with variation in dose and dilution as dictated by the condition of the individual patient. Subsequent dosage, dilution, and frequency of injections are best judged by the clinical response. Intralesional or Sublesional Average Dose Up to 0.5 mg per square inch of affected skin injected intralesionally or sublesionally. The frequency of subsequent injections is best determined by the clinical response. If desired, the vial may be diluted as indicated under Directions for Use. A lesser initial dosage range of Aristospan may produce the desired effect when the drug is administered to provide a localized concentration. The site of the injection and the volume of the injection should be carefully considered when Aristospan is administered for this purpose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 15 HOW SUPPLIED Aristospan® (triamcinolone hexacetonide injectable suspension, USP), 5 mg/mL is available as follows: NDC 0781-3084-75 5 mL fill in a 10 mL vial Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Protect from light. DO NOT FREEZE. 07-2008M U1006743 Manufactured in Canada by Sandoz Canada Inc. for Sandoz Inc., Princeton, NJ 08540 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda St r u ctural Formula NDA 16-466/S-040 NDA 16-466/S-041 Page 16 Aristospan® (Triamcinolone Hexacetonide Injectable Suspension, USP) 20 mg/mL PARENTERAL NOT FOR USE IN NEWBORNS FOR INTRA-ARTICULAR USE NOT FOR INTRAVENOUS USE DESCRIPTION A sterile suspension containing 20 mg/mL of micronized triamcinolone hexacetonide in the following inactive ingredients: Polysorbate 80 NF 0.40% w/v Sorbitol Solution USP 50.00% w/v Water for Injection qs ad 100.00% V Hydrochloric Acid and Sodium Hydroxide, if required, to adjust pH to 4.0-8.0 Preservative: Benzyl Alcohol 0.90% w/v Chemically triamcinolone hexacetonide USP is 9α-Fluoro-11β,16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone 21-(3,3-dimethylbutyrate). Molecular weight is 532.65. The structural formula is: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 17 CLINICAL PHARMACOLOGY Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders of many organ systems. When injected intra-articularly, triamcinolone hexacetonide can be expected to be absorbed slowly from the injection site. INDICATIONS AND USAGE The intra-articular or soft tissue administration of Aristospan (triamcinolone hexacetonide injectable suspension, USP) 20 mg/mL is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. CONTRAINDICATIONS Aristospan is contraindicated in patients who are hypersensitive to any components of this product. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. WARNINGS General This product contains benzyl alcohol. Benzyl alcohol has been associated with a fatal “Gasping Syndrome” in premature infants and infants of low birth weight. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS: Pediatric Use). Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS). Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation. Results from one multicenter, randomized, placebo controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of corticosteroids, including Aristospan®, should not be used for the treatment of traumatic brain injury. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 18 Cardio-renal Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Infections General Patients who are on corticosteroids are more susceptible to infections than healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS: Drug Interactions: Amphotericin B Injection and Potassium-Depleting Agents). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Corticosteroids should not be used in cerebral malaria. Tuberculosis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 19 If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccination Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease. Viral Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered. Neurologic Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS: Gastrointestinal and Neurologic/Psychiatric). Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroids should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Atrophy at the site of injection has been reported. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 20 Cardio-renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Gastrointestinal Steroids should be used with caution in active or latent peptic ulcer, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Intra-articular and Soft Tissue Administration Intra-articularly injected corticosteroids may be systemically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS: Musculoskeletal). Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy. Neuro-psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 21 An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Information for Patients Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions Aminoglutethimide Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B Injection and Potassium-Depleting Agents When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, Oral Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 22 Antidiabetics Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular Drugs Serum concentrations of isoniazid may be decreased. Cholestyramine Cholestyramine may increase the clearance of corticosteroids. Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis Glycosides Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including Oral Contraceptives Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin) Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects. Nonsteroidal Anti-Inflammatory Agents (NSAIDs) Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin Tests Corticosteroids may suppress reactions to skin tests. Vaccines Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections: Vaccination). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 23 Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 24 Pregnancy Teratogenic Effects Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman. Pediatric Use This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low- birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 25 Geriatric Use No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS (listed alphabetically, under each subsection) Allergic Reactions Anaphylactoid reactions, anaphylaxis, angioedema. Cardiovascular Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetics, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness, (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and Electrolyte Disturbances Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 26 Negative nitrogen balance due to protein catabolism. Musculoskeletal Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot- like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS: Infections: Neurologic). Ophthalmic Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 27 OVERDOSAGE Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS) General The initial dosage of Aristospan (triamcinolone hexacetonide injectable suspension, USP) may vary from 2 to 48 mg per day depending on the specific disease entity being treated. However, in certain overwhelming, acute, life- threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. It Should Be Emphasized That Dosage Requirements are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long- term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. In pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in three or four divided doses (3.2 to 48 mg/m2bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. Directions for Use Strict aseptic administration technique is mandatory. Topical ethylchloride spray may be used locally before injection. The syringe should be gently agitated to achieve uniform suspension before use. Since this product has been designed for ease of administration, a small bore needle (not smaller than 23 gauge) may be used. Dilution This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-466/S-040 NDA 16-466/S-041 Page 28 Aristospan suspension may be mixed with 1% or 2% Lidocaine Hydrochloride, using the formulations which do not contain parabens. Similar local anesthetics may also be used. Diluents containing methylparaben, propylparaben, phenol, etc., should be avoided since these compounds may cause flocculation of the steroid. These dilutions will retain full potency for one week, but care should be exercised to avoid contamination of the vial’s contents and the dilutions should be discarded after 7 days. Intra-articular Average dose - 2 to 20 mg (0.1 mL to 1 mL) The dose depends on the size of the joint to be injected, the degree of inflammation, and the amount of fluid present. In general, large joints (such as knee, hip, shoulder) require 10 to 20 mg. For small joints (such as interphalangeal, metacarpophalangeal), 2 to 6 mg, may be employed. When the amount of synovial fluid is increased, aspiration may be performed before administering Aristospan. Subsequent dosage and frequency of injection can best be judged by clinical response. The usual frequency of injection into a single joint is every three or four weeks, and injection more frequently than that is generally not advisable. To avoid possible joint destruction from repeated use of intra-articular corticosteroids, injection should be as infrequent as possible, consistent with adequate patient care. Attention should be paid to avoiding deposition of drug along the needle path which might produce atrophy. HOW SUPPLIED Aristospan® (triamcinolone hexacetonide injectable suspension, USP), 20 mg/mL is available as follows: NDC 0781-3085-71 1 mL fill in a 2 mL vial NDC 0781-3085-75 5 mL fill in a 10 mL vial Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Protect from light. DO NOT FREEZE. 07-2008M U1006746 Manufactured in Canada by Sandoz Canada Inc. for Sandoz Inc., Princeton, NJ 08540 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:43:59.934663	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016466s040s041lbl.pdf', 'application_number': 16466, 'submission_type': 'SUPPL ', 'submission_number': 40}
10,895	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:00.223030	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/16584s55s47lbl.pdf', 'application_number': 16584, 'submission_type': 'SUPPL ', 'submission_number': 47}
10,896	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:00.244469	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/16584s55s47lbl.pdf', 'application_number': 16584, 'submission_type': 'SUPPL ', 'submission_number': 56}
10,894	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SODIUM IODIDE I 131 CAPSULES THERAPEUTIC safely and effectively. See full prescribing information for SODIUM IODIDE I 131 CAPSULES THERAPEUTIC. SODIUM IODIDE I 131 CAPSULES THERAPEUTIC for oral use Initial U.S. Approval: 1971 ---------------------------RECENT MAJOR CHANGES --------------------------- Contraindications (4) 03/2014 ----------------------------INDICATIONS AND USAGE --------------------------- Sodium Iodide I 131 Capsules Therapeutic is a radioactive therapeutic agent indicated for the treatment of hyperthyroidism and thyroid carcinomas that take up iodine. Palliative effects may be observed in patients with advanced thyroid malignancy if the metastatic lesions take up iodine. (1) ----------------------- DOSAGE AND ADMINISTRATION ---------------------- Use safe handling measures to minimize inadvertent radiation exposure. (2.1) Hyperthyroidism • 148 to 370 megabecquerels (MBq) (4 to 10 millicuries, mCi). Toxic nodular goiter and other situations may require larger doses. (2.2) Thyroid Carcinoma • For thyroid carcinoma, 3700 to 5550 MBq (100 to 150 mCi). (2.3) • For post-operative ablation of normal thyroid tissue: 1850 MBq (50 mCi). (2.3) Individualize therapy, including dose selection, based upon patient- specific factors detected during the therapeutic planning process. (2.4) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Capsules: available in 15 strengths from 0.75 mCi to 100 mCi at the time of calibration. See full prescribing information for details. (3) -------------------------------CONTRAINDICATIONS ------------------------------ • Patients with vomiting and diarrhea (4) • Treatment of thyroid malignancies shown to have no iodide uptake (4) • Pregnancy (4) • Breastfeeding (4) ----------------------- WARNINGS AND PRECAUTIONS----------------------- • Radiation-induced thyroiditis: may cause or worsen hyperthyroidism; consider pre-treatment with anti-thyroid medications. (5.1) • Thyroid enlargement, including that due to thyroid stimulating hormone concomitant therapy, may obstruct structures in the neck. Evaluate patients at high risk. (5.2) • Multiple non-thyroid radiation toxicities have been reported following sodium iodide I-131 therapy, including increased risks for neoplasia, hematopoietic suppression, and fetal or reproductive toxicity. Individualize dosage, verify absence of pregnancy, monitor patients for toxicity, and advise patients on contraceptive use. (5.3, 5.5, 5.6) ------------------------------ ADVERSE REACTIONS ----------------------------- • Adverse reactions that have been reported with doses of sodium iodide I-131 used in the treatment of benign disease include sialadenitis, chest pain, tachycardia, iododerma, itching skin, rash, hives, hypothyroidism, hyperthyroidism, thyrotoxic crisis, hypoparathyroidism, and local swelling. (6) • Adverse reactions that have been reported with doses of sodium iodide I-131 used in the treatment of malignant disease include radiation sickness, bone marrow depression, anemia, leucopenia, thrombocytopenia, blood dyscrasia, leukemia, solid cancers, lacrimal gland dysfunction, salivary gland dysfunction, congenital hypothyroidism, and chromosomal abnormalities, cerebral edema, radiation pneumonitis, and pulmonary fibrosis. (6) To report SUSPECTED ADVERSE REACTIONS contact Mallinckrodt Inc. at 1-888-744-1414 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------------------------------DRUG INTERACTIONS ------------------------------ Many pharmacologic agents are known to interact with radioiodide. See full prescribing information complete list. (7) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Nursing Mothers: to minimize the absorbed radiation dose to breast tissue, discontinue breastfeeding at least four weeks before sodium iodide I-131 therapy. If administered in the postpartum period, the lactating mother should not breast-feed. (8.3) • Pediatric Use: safety and effectiveness in pediatric patients have not been established. (8.4) • Geriatric Use: enhanced evaluation, dose selection and follow-up procedures may be necessary for geriatric patients due to underlying co-morbidities, including renal dysfunction. (8.5) • Renal Impairment: may increase radiation exposure. (8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised 10/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Radiation Safety 2.2 Hyperthyroidism 2.3 Thyroid Carcinoma 2.4 Individualization of Therapy 2.5 Radiation Dosimetry 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Radiation-induced Thyroiditis 5.2 Thyroid-stimulating Hormone (TSH) and Thyroid Enlargement 5.3 Radiation-induced Toxicities 5.4 Hypersensitivity Reactions 5.5 Fetal Risk 5.6 Transient Infertility 5.7 Radiation Exposure Risk to Other Individuals 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 11.1 Physical Characteristics 11.2 External Radiation 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Page 1 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Sodium Iodide I 131 Capsules Therapeutic is indicated for the treatment of hyperthyroidism and thyroid carcinomas that take up iodide. Palliative effects may be observed in patients with advanced thyroid malignancy if the metastatic lesions take up iodide. 2 DOSAGE AND ADMINISTRATION 2.1 Radiation Safety Sodium iodide I-131 capsules emit radiation and must be handled with safety measures to minimize inadvertent radiation exposure to clinical personnel and patients [see Warnings and Precautions (5.7)]. • Radiopharmaceuticals should be used only by or under the direction of physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. • Wear waterproof gloves during the entire sodium iodide I-131 capsule handling and administration procedure. • Maintain adequate shielding during the radiation-emitting life of the product. • Measure the patient dose using a suitable radioactivity calibration system immediately prior to administration. 2.2 Hyperthyroidism For hyperthyroidism, the usual sodium iodide I-131 dose range is 148 to 370 MBq (4 to 10 mCi). Higher doses may be necessary for the treatment of toxic nodular goiter and other special situations. Consider discontinuation of anti-thyroid therapy in a severely hyperthyroid patient three to four days before administration of sodium iodide I-131. Evaluate patients for risk of thyroid enlargement and obstruction of structures in the neck [see Warnings and Precautions (5.1, 5.2)]. 2.3 Thyroid Carcinoma For thyroid carcinoma, the usual sodium iodide I-131 therapeutic dose is 3700 to 5550 MBq (100 to 150 mCi). For ablation of post-operative residual thyroid tissue, the usual dose is 1850 MBq (50 mCi). 2.4 Individualization of Therapy Individualize sodium iodide I-131 therapy, including dose selection, based upon patient- specific factors such as the nature of the underlying condition, co-morbidities, age, estimated thyroid tissue iodine uptake, thyroid size, as well as ability of the patient to comply with the therapeutic regimen and radiation safety procedures. Perform a clinical assessment, including history, physical examination and laboratory testing when preparing patients for sodium iodide I-131 therapy in order to detect conditions which Page 2 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda may alter thyroid iodine uptake and increase the risks of the therapy or diminish its effectiveness. For example, intake of iodine in radiographic contrast may diminish thyroid iodine uptake while low serum chloride or nephrosis may increase thyroid iodine uptake. Obtain a drug history and ascertain whether any medications need to be withheld before the administration of the therapy [see Drug Interactions (7)]. 2.5 Radiation Dosimetry The estimated absorbed radiation doses1 to an average (70 kg) euthyroid (normal functioning thyroid) patient from an oral dose of iodine-131 in both milligray (mGy) per megabecquerel (MBq) and rad per millicurie (mCi) are shown in Table 1. Table 1. Absorbed Radiation Doses Tissue Thyroid Uptake 5% 15% 25% mGy/ MBq rads/ mCi mGy/ MBq rads/ mCi mGy/ MBq rads/ mCi Thyroid Stomach Wall Red Marrow Liver Testes Ovaries Urinary Bladder Salivary Glands2 Other 72 0.45 0.038 0.03 0.029 0.044 0.58 0.5 0.040 266 1.7 0.14 0.11 0.11 0.16 2.1 1.85 0.15 210 0.46 0.054 0.032 0.028 0.043 0.52 0.5 0.065 777 1.7 0.20 0.12 0.10 0.16 1.9 1.85 0.24 360 0.46 0.07 0.035 0.027 0.043 0.46 0.5 0.090 1300 1.7 0.26 0.13 0.10 0.16 1.7 1.85 0.33 3 DOSAGE FORMS AND STRENGTHS Sodium Iodide I 131 Capsules Therapeutic are opaque white capsules supplied in multiple strengths (Table 2). Page 3 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2. Capsule Strengths Strengths Available Total Radioactivity per Capsule (* At time of calibration) 28 MBq (0.75 mCi) 74 MBq (2 mCi) 111 MBq (3 mCi) 148 MBq (4 mCi) 185 MBq (5 mCi) 222 MBq (6 mCi) 259 MBq (7 mCi) 296 MBq (8 mCi) 370 MBq (10 mCi) 444 MBq (12 mCi) 555 MBq (15 mCi) 629 MBq (17 mCi) 740 MBq (20 mCi) 1850 MBq (50 mCi) 3700 MBq (100 mCi) 4 CONTRAINDICATIONS Sodium Iodide I 131 Capsules Therapeutic is contraindicated in: • Patients with vomiting and diarrhea [see Warnings and Precautions (5.7)]. • The treatment of thyroid malignancies shown to have no iodide uptake, which include the majority of medullary and anaplastic carcinomas. • Pregnancy [see Warnings and Precautions (5.5)]. • Breastfeeding [see Use in Specific Populations (8.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Radiation-induced Thyroiditis Sodium iodide I-131 may cause thyroiditis with gland enlargement and release of thyroid hormone, particularly when used to treat hyperthyroidism. The thyroiditis may cause or worsen hyperthyroidism, and may cause thyroid storm. When treating hyperthyroidism, consider pre-treatment with anti-thyroid medication to help deplete the thyroid hormone content within the gland. Discontinue the anti-thyroid medication at least three days before administration of sodium iodide I-131. Consider beta-blocker therapy before administration of sodium iodide I-131 to minimize the risk of hyperthyroidism and thyroid storm. Page 4 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.2 Thyroid-stimulating Hormone (TSH) and Thyroid Enlargement Enhanced TSH secretion, e.g., following discontinuation of anti-thyroid medications, or the administration of TSH to enhance sodium iodide I-131 uptake, may cause thyroid enlargement and obstructive complications of the trachea, esophagus, or blood vessels in the neck. Evaluate patients at high risk of obstructive complications before preparative treatments known to cause thyroid enlargement. 5.3 Radiation-induced Toxicities Radiation-induced toxicities, including dose-dependent fatalities, have been reported following sodium iodide I-131 therapy. Post-marketing reports have identified an increased risk for neoplasia, as well as risks for hematopoietic suppression. Salivary and lacrimal gland toxicity is relatively common and may manifest as conjunctivitis, xerophthalmia, epiphora, sialadenitis and xerostomia [see Adverse Reactions (6)]. 5.4 Hypersensitivity Reactions Hypersensitivity reactions, including rash and hives have been reported following administration of sodium iodide I-131. Sodium iodide I-131 capsules may contain sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. During the pre-therapy assessment, question patients about a history of hypersensitivity to sulfite [see Adverse Reactions (6)]. 5.5 Fetal Risk Transplacental passage of sodium iodide I-131 can cause severe and possibly irreversible hypothyroidism in neonates [see Contraindications (4)]. Females and Males of Childbearing Potential When planning sodium iodide I-131 therapy for women of childbearing potential, obtain a pregnancy test and verify the absence of a pregnancy before initiating treatment. Advise women and men of childbearing potential to use two effective methods of contraception to avoid pregnancy for at least six months after sodium iodide I-131 administration. Advise patients of the potential need to use two effective methods of contraception to avoid pregnancy for an even longer period of time (e.g., one year) if additional sodium iodide I-131 therapy or radionuclide imaging is anticipated. 5.6 Transient Infertility Transient, dose-related impairment of testicular function has been reported after sodium iodide I-131 therapy. Consider sperm banking for men who are anticipated to receive a high cumulative sodium iodide I-131 dose (e.g., greater than 14 GBq). In females, transient ovarian failure has been observed after sodium iodide I-131 therapy. Page 5 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.7 Radiation Exposure Risk to Other Individuals Unwanted radiation exposure can occur from handling and administration of radiopharmaceuticals or from contaminated waste products, including urine and feces. Follow safe administration instructions to minimize unnecessary radiation exposure to patients and health care workers [see Dosage and Administration (2.1)]. Instruct patients on how to reduce unnecessary radiation exposure to others, especially family members following treatment. Review the most recent professional society guidelines and publications that describe the procedures for the safe use of sodium iodide I-131 therapy to minimize radiation toxicity risks to patients, radiation exposure risks to other individuals, and environmental radiation contamination risks. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: • Radiation-induced Thyroiditis [see Warnings and Precautions (5.1)] • Thyroid-stimulating Hormone and Thyroid Enlargement [see Warnings and Precautions (5.2)] • Radiation-induced Toxicities [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions [see Warnings and Precautions (5.4)] • Fetal Risk [see Warnings and Precautions (5.5)] • Transient Infertility [see Warnings and Precautions (5.6)] • Radiation Exposure to Other Individuals [see Warnings and Precautions (5.7)] Radiation-related adverse reactions are a function of the dose level received by the patient. The following adverse reactions have been reported with doses of sodium iodide I-131 used in the treatment of benign disease, such as hyperthyroidism: • Gastrointestinal disorders: sialadenitis • Cardiac disorders: chest pain and tachycardia • Skin and subcutaneous tissue disorders: iododerma, itching skin, rash, and hives • Endocrine disorders: hypothyroidism, hyperthyroidism, thyrotoxic crisis, hypoparathyroidism • General disorders and administration site conditions: local swelling The following adverse reactions have been reported with doses of sodium iodide I-131 used in the treatment of malignant disease: Page 6 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Blood and lymphatic system disorders including fatalities: radiation sickness, bone marrow depression, anemia, leucopenia, thrombocytopenia, and blood dyscrasia • Neoplasms benign, malignant and unspecified (including cysts and polyps): leukemia and solid cancers • Eye disorders: lacrimal gland dysfunction • Gastrointestinal disorders: salivary gland dysfunction, nausea, vomiting • Congenital, familial and genetic disorders: congenital hypothyroidism and chromosomal abnormalities • Nervous System Disorders: Cerebral edema • Pulmonary Disorders: Radiation pneumonitis, Pulmonary fibrosis In patients with iodine-avid brain metastases *In patients with iodine-avid lung metastases Adverse reactions that occur after treatment of benign disease may also occur after treatment of malignant disease. Tenderness, pain on swallowing, sore throat, and cough have been reported, generally around the third day after sodium iodide I-131 administration. 7 DRUG INTERACTIONS Many pharmacologic agents interact with sodium iodide I-131. These agents may affect the iodide protein binding and alter the iodide pharmacokinetics and pharmacodynamics. Page 7 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3. Drug Interactions Substance Average Duration of Effect Anti-thyroid drugs e.g., carbimazole, propylthiouracil 5 days Natural or synthetic thyroid hormone e.g., thyroxine tri-iodothyronine 4 weeks 2 weeks Iodine-containing medications e.g., amiodarone expectorants, vitamins 4 weeks 2 weeks Topical iodide 1-9 months X-ray contrast agents iodine-containing agents Up to 1 year Other drugs anticoagulants, antihistamines corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium 1 week 1 week 1 week 1-2 weeks 4 weeks 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Warnings and Precautions (5.5)]. 8.3 Nursing Mothers Sodium iodide I-131 is excreted into human milk and may reach concentrations equal to or greater than concentrations in maternal plasma. To minimize the absorbed radiation dose to the breast tissue, breastfeeding and breast-pumping should be discontinued for at least four weeks before administration of sodium iodide I-131. Sodium iodide I-131 is contraindicated in pregnancy; if sodium iodide I-131 is administered in the postpartum period, the lactating mother should not breast-feed the infant. Breastfeeding may resume with the birth of another child, if the mother does not receive sodium iodide I-131 during that postpartum period. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Published reports suggest that the thyroid gland of pediatric patients is more sensitive to the effects of sodium iodide I-131; however, it is unknown if the I-131 dose-response relationship is similar to that of adults. When considering the use of sodium iodide I-131 in pediatric patients, the risks, particularly carcinogenic risks, and benefits of sodium iodide I-131 must be carefully weighed against those of other possible treatments. Page 8 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.5 Geriatric Use Because elderly patients are more likely to have decreased renal function and co morbid conditions, enhanced evaluation, dose-selection consideration and follow-up may be necessary for elderly patients receiving sodium iodide I-131 therapy, compared to younger patients [see Use in Specific Populations (8.6)]. When treating hyperthyroidism in geriatric patients at risk of developing cardiac complications, pre-treatment and post-treatment with anti-thyroid drugs and/or beta- blockers may help minimize the risk of excessive post-treatment hyperthyroidism due to radiation-induced thyroiditis [see Warnings and Precautions (5.1)]. 8.6 Renal Impairment Sodium iodide I-131 is eliminated predominantly through renal clearance. Patients with renal impairment are subject to decreased excretion of sodium iodide I-131 and increased radiation exposure. Evaluate renal function for therapeutic planning [see Dosage and Administration (2.4)]. Sodium iodide I-131 is dialyzable. Hemodialysis can be used to reduce total body radiation exposure. 10 OVERDOSAGE In case of exposure to a radioactive dose of sodium iodide I-131 exceeding the intended therapeutic dose provide general supportive care, monitor for bone marrow and thyroid suppression and consider administering a thyroid blocking agent such as potassium iodide (KI) or perchlorate promptly within 4 to 6 hours after the exposure. Thyroid blockade may reduce radiation exposure of thyroid tissue but would not prevent radiation injury to the rest of the body. Assess the benefit of administering a blocking agent against the risk of failure of sodium iodide I-131 therapy. 11 DESCRIPTION Sodium Iodide I 131 (Na I-131) Capsules Therapeutic is supplied for oral administration in opaque white gelatin capsules. The capsules are available in strengths ranging from 28 to 3700 MBq (0.75 to 100 mCi) iodine-131 at the time of calibration. Sodium iodide I-131 capsules are packaged in shielded, plastic vials containing one capsule per vial. Sodium iodide I-131 capsules are prepared by absorbing a solution of carrier-free sodium iodide I-131 that may contain sodium bisulfite into inert filler. The iodine-131 utilized in the preparation of the capsules contains not less than 99% iodine-131 at the time of calibration. The calibration date and the expiration date are stated on the label. 11.1 Physical Characteristics Iodine-131 decays by beta emission and associated gamma emission with a physical half-life of 8.02 days3. The principal beta emissions and gamma photons are listed in Table 4. Page 9 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4. Principal Radiation Emission Data Mean Percent Radiation Per Energy (keV) Disintegration Beta-1 2.10 69.4 Avg. Beta-3 7.27 96.6 Avg. Beta-4 89.9 191.6 Avg. Gamma-7 6.14 284.3 Gamma-14 81.7 364.5 Gamma-17 7.17 637.0 11.2 External Radiation The specific gamma ray constant for iodine-131 is 2.20 R/hr-mCi at 1 cm. The first half- value thickness of lead (Pb) for iodine-131 is 0.27 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 5. For example, the use of 4.5 cm of Pb will decrease the external radiation exposure by a factor of about 1,000. Table 5. Radiation Attenuation by Lead Shielding4 Shield Thickness (Pb), cm Coefficient of Attenuation 0.27 0.99 2.6 4.5 0.5 10-1 10-2 10-3 To correct for physical decay of this radionuclide, the fractions that remain at selected time intervals after the date of calibration are shown in Table 6. Page 10 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 6. Physical Decay Chart Iodine-131: Half-Life 8.02 Days Fraction Fraction Days Remaining Days Remaining 0 1.000 9 0.459 1 0.917 10 0.421 2 0.841 11 0.387 3 0.772 12 0.355 4 0.708 13 0.325 5 0.649 14 0.298 6 0.595 15 0.274 7 0.546 16 0.251 8 0.501 17 0.230 *Calibration Day 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Taken orally, sodium iodide I-131 is rapidly absorbed and distributed within the extracellular fluid of the body. The iodide is concentrated in the thyroid via the sodium/iodide symporter, and subsequently oxidized to iodine. The destruction of thyroidal tissue is achieved by the beta emission of sodium iodide I-131. 12.2 Pharmacodynamics The therapeutic effects of sodium iodide I-131 are a result of the ionizing radiation absorbed by the thyroidal tissue. Tissue damage is the result of direct insult to molecules by ionization and excitation and the consequent dissociation of those molecules. About 90% of local irradiation from sodium iodide I-131 is the result of beta radiation and 10% is the result of gamma radiation. 12.3 Pharmacokinetics After oral administration, sodium iodide I-131 is absorbed rapidly from the upper gastrointestinal tract (90% in 60 minutes). The pharmacokinetics follow that of unlabelled iodide. After entering the blood stream, the iodide is distributed into the extra thyroidal compartment. From here it is predominantly taken up by the thyroid or excreted renally. In the thyroid, the trapped iodide is oxidized to iodine and organified. The sodium/iodide symporter (NIS) is responsible for the concentration of iodide in the thyroid. This active transport process concentrates iodide 20 to 40 times the plasma concentration under normal circumstances, and this may increase tenfold in the hyperthyroid state. NIS also mediates active iodide transport in other tissues, including salivary glands, nasolacrimal duct, lacrimal sac, gastric mucosa, lactating mammary Page 11 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda gland, and the choroid plexus. The non-thyroidal iodide transporting tissues do not have the ability to organify accumulated iodide. Depending on renal and thyroid gland function, urinary excretion is 37 to 75% of the administered dose, fecal excretion is about 10%, and excretion in sweat is almost negligible. 15 REFERENCES 1 International Commission on Radiological Protection. Radiation Dose to Patients from Radiopharmaceuticals. ICRP Publication 53, Pergamon Press, New York, NY, 1988. 2 L. Johansson, S. Leide-Svegborn, S. Matteson, B. Nosslin. Biokinetics of Iodide in Man: Refinement of Current ICRP Dosimetry Models. Cancer Biotherapy & Radiopharmaceuticals, 18(3): 445-450, 2003. 3 Stabin MG, da Luz CQPL. Decay Data for Internal and External Dose Assessment, Health Phys. 83(4):471-475, 2002. 4 Smith David S., Stabin, Michael G. Exposure Rate Constants and Lead Shielding Values for Over 1,100 Radionuclides, Health Physics. 102(3):271-291, March 2012. 16 HOW SUPPLIED/STORAGE AND HANDLING Sodium Iodide I 131 Capsules Therapeutic is supplied in a shielded, plastic vial containing one opaque white gelatin capsule per vial. The capsules are available in strengths ranging from 28 to 3700 MBq (0.75 to 100 mCi) iodine-131 at the time of calibration. The calibration date and the expiration date are stated on the label. Do not use the product after the expiration date. Page 12 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sodium Iodide I 131 Capsules for Therapeutic Use NDC mCi Capsule 0019-9452-75 0.75 0019-9452-02 2 0019-9452-03 3 0019-9452-04 4 0019-9452-05 5 0019-9452-06 6 0019-9452-07 7 0019-9452-08 8 0019-9452-10 10 0019-9452-12 12 0019-9452-15 15 0019-9452-17 17 0019-9452-20 20 0019-9452-50 50 0019-9452-00 100 Storage Store at a controlled room temperature of 20° to 25°C (68° to 77°F). Storage and disposal of Sodium Iodide I 131 Capsules Therapeutic should be controlled in a manner that is in compliance with the appropriate regulations of the government agency authorized to license the use of this radionuclide. The U.S. Nuclear Regulatory Commission has approved distribution of this radiopharmaceutical to persons licensed to use byproduct material listed in 10 CFR 35.300, and to persons who hold an equivalent license issued by an Agreement State. 17 PATIENT COUNSELING INFORMATION Review the most recent professional society guidelines and publications that describe important components of the patient counseling process. • Discuss the measures to minimize inadvertent radiation exposure to the patient, members of the patient’s household, the public, and the environment. • Advise females and males of reproductive potential of the need to use two effective methods of contraception to avoid pregnancy for at least 6 months after I-131 administration due to fetal risk. Advise patients of the potential need to use two effective methods of contraception to avoid pregnancy for an even longer period of time (e.g., one year) if additional sodium iodide I-131 therapy and further radionuclide imaging is anticipated. • Advise patients of the possibility of transient infertility and possible use of sperm banking for males of reproductive potential. Page 13 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Among lactating females, discuss the need to discontinue breastfeeding and pumping at least four weeks before administration of sodium iodide I-131. If sodium iodide I-131 is administered in the postpartum period, advise the lactating mother to not breastfeed her infant. Manufactured by: Mallinckrodt Inc. St. Louis, MO 63134 USA A452I0 Rev 10/2015 company logo Page 14 of 14 Reference ID: 3835445 102015-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:00.318479	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/016517s013lbl.pdf', 'application_number': 16517, 'submission_type': 'SUPPL ', 'submission_number': 13}
10,899	Page 3 Tegretol® carbamazepine USP Chewable Tablets of 100 mg - red-speckled, pink Tablets of 200 mg – pink Suspension of 100 mg/5 mL Tegretol®-XR (carbamazepine extended-release tablets) 100 mg, 200 mg, 400 mg Rx only Prescribing Information WARNING SERIOUS DERMATOLOGIC REACTIONS AND HLA-B1502 ALLELE SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT- RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS/LABORATORY TESTS). APLASTIC ANEMIA AND AGRANULOCYTOSIS APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA. ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS. BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS. Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential. DESCRIPTION Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and its structural formula is Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. Inactive Ingredients. Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only). CLINICAL PHARMACOLOGY In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia. Mechanism of Action Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown. The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been established. Pharmacokinetics In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol. The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age). The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 INDICATIONS AND USAGE Epilepsy Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: 1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types. 2. Generalized tonic-clonic seizures (grand mal). 3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General). Trigeminal Neuralgia Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains. CONTRAINDICATIONS Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits. WARNINGS Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. SJS/TEN and HLA-B1502 Allele Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity. Across Asian populations, notable variation exists in the prevalence of HLA-B1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 Indians, appear to have intermediate prevalence of HLA-B1502, averaging 2 to 4%, but higher in some groups. HLA-B1502 is present in <1% of the population in Japan and Korea. HLA-B1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African- Americans, Hispanics, and Native Americans). Prior to initiating Tegretol therapy, testing for HLA-B1502 should be performed in patients with ancestry in populations in which HLA-B1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients positive for HLA-B1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS/Laboratory Tests). Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on Tegretol. The HLA-B1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Tegretol, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption [MPE]). Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other anti-epileptic drugs associated with SJS/TEN. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA- B1502 positive patients, when alternative therapies are otherwise equally acceptable. Application of HLA-B1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B1502- positive Asian patients treated with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in HLA-B1502-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied. Aplastic Anemia and Agranulocytosis Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression General Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy. Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria. As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased seizure frequency. Usage in Pregnancy Carbamazepine can cause fetal harm when administered to a pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. In treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women. In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung. Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg. Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may represent a neonatal withdrawal syndrome. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 PRECAUTIONS General Before initiating therapy, a detailed history and physical examination should be made. Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE). Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol. AV heart block, including second and third degree block, have been reported following, Tegretol treatment. This occurred generally, but not solely, in patients with underling EKG abnormalities or risk factors for conduction disturbances. Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug. Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients). Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops. Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If positive, caution should be used in prescribing carbamazepine. Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION). Information for Patients Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or non-prescription medications or herbal products. Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive sedative effect. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks. Laboratory Tests For genetically at-risk patients (See WARNINGS), high-resolution ‘HLA-B1502 typing’ is recommended. The test is positive if either one or two HLA-B1502 alleles are detected and negative if no HLA-B1502 alleles are detected. Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease. Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes. Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction. Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used. Thyroid function tests have been reported to show decreased values with Tegretol administered alone. Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other drugs. Interference with some pregnancy tests has been reported. Drug Interactions There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine® solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents. (see Dosage and Administration). Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 Agents That May Affect Tegretol Plasma Levels CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole), acetazolamide, verapamil, grapefruit juice, protease inhibitors, valproate. CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl, felbamate,† rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline. When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required. increased levels of the active 10,11-epoxide †decreased levels of carbamazepine and increased levels of the 10,11-epoxide Effect of Tegretol on Plasma Levels of Concomitant Agents Increased levels: clomipramine HCl, phenytoin, primidone Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to cause, decreased levels of the following: acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine), cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine, dicumarol, doxycycline, ethosuximide, haloperidol, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, theophylline, tiagabine, topiramate, tramadol, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin,ziprasidone, zonisamide. In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary. Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of carbamazepine with nefazodone is contraindicated. (See CONTRAINDICATIONS). Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications. Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 Carcinogenesis, Mutagenesis, Impairment of Fertility Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males. Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown. Usage in Pregnancy Pregnancy Category D (see WARNINGS). Labor and Delivery The effect of Tegretol on human labor and delivery is unknown. Nursing Mothers Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to the newborn during breast feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the epoxide. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see Indications for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children. Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults. The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available. Geriatric Use No systematic studies in geriatric patients have been conducted. ADVERSE REACTIONS If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 The most severe adverse reactions have been observed in the hemopoietic system (see boxed WARNING), the liver and the cardiovascular system. The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the low dosage recommended. The following additional adverse reactions have been reported: Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria. Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear. Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy. Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds. Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure. Pancreatic: Pancreatitis. Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia. Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown. Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, and hyperacusis. There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of psychotropic drugs. Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 Eyes: Scattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes. Musculoskeletal System: Aching joints and muscles, and leg cramps. Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium have been reported. Other: Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests. These signs and symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and PRECAUTIONS, Information for Patients). Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants. A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine. DRUG ABUSE AND DEPENDENCE No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or physical dependence in humans. OVERDOSAGE Acute Toxicity Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year- old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia). Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920. Signs and Symptoms The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (> 60 g) have been ingested. Respiration: Irregular breathing, respiratory depression. Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders. Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia. Gastrointestinal Tract: Nausea, vomiting. Kidneys and Bladder: Anuria or oliguria, urinary retention. Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias. Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified. Treatment The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote. Elimination of the Drug: Induction of vomiting. Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol. Measures to Reduce Absorption: Activated charcoal, laxatives. Measures to Accelerate Elimination: Forced diuresis. Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children. Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen. Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered. Convulsions: Diazepam or barbiturates. Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week). Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days. Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery. Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 16 A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought. DOSAGE AND ADMINISTRATION (see table below) Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in the stool following coadministration of the two drugs. (See Drug Interactions). Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medications or diluents. Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. Medication should be taken with meals. Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase slowly to avoid unwanted side effects. Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d. suspension). Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be noticeable in the stool. Epilepsy (see INDICATIONS AND USAGE) Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily. Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level, usually 400-800 mg daily. Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 17 whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be made. Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug Interactions, and Pregnancy Category D). Trigeminal Neuralgia (see INDICATIONS AND USAGE) Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 18 Dosage Information Initial Dose Subsequent Dose Maximum Daily Dose Indication Tablet XR † Suspension Tablet* XR † Suspension Tablet* XR † Suspension Epilepsy Under 6 yr 10-20 mg/kg/day b.i.d. or t.i.d. 10-20 mg/kg/day q.i.d. Increase weekly to achieve optimal clinical response, t.i.d. or q.i.d. Increase weekly to achieve optimal clinical response, t.i.d. or q.i.d. 35 mg/kg/24 hr (see Dosage and Administration section above) 35 mg/kg/24 hr (see Dosage and Administration section above) 6-12 yr 100 mg b.i.d. (200 mg/day) 100 mg b.i.d. (200 mg/day) ½ tsp q.i.d. (200 mg/day) Add up to 100 mg/day at weekly intervals, t.i.d. or q.i.d. Add 100 mg/day at weekly intervals, b.i.d. Add up to 1 tsp (100 mg)/day at weekly intervals, t.i.d. or q.i.d. 1000 mg/24 hr Over 12 yr 200 mg b.i.d. (400 mg/day) 200 mg b.i.d. (400 mg/day) 1 tsp q.i.d. (400 mg/day) Add up to 200 mg/day at weekly intervals, t.i.d. or q.i.d. Add up to 200 mg/day at weekly intervals, b.i.d. Add up to 2 tsp (200 mg)/day at weekly intervals, t.i.d. or q.i.d. 1000 mg/24 hr (12-15 yr) 1200 mg/24 hr (>15 yr) 1600 mg/24 hr (adults, in rare instances) Trigeminal Neuralgia 100 mg b.i.d. (200 mg/day) 100 mg b.i.d. (200 mg/day) ½ tsp q.i.d. (200 mg/day) Add up to 200 mg/day in increments of 100 mg every 12 hr Add up to 200 mg/day in increments of 100 mg every 12 hr Add up to 2 tsp (200 mg)/day in increments of 50 mg (½ tsp) q.i.d. 1200 mg/24 hr *Tablet = Chewable or conventional tablets †XR = Tegretol ®-XR extended-release tablets This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52 twice on the scored side) Bottles of 100.........................................................................................NDC 0083-0052-30 Unit Dose (blister pack) Box of 100 (strips of 10)..................................................................NDC 0083-0052-32 Do not store above 30°C (86°F). Protect from light and moisture. Dispense in tight, light-resistant container (USP). Meets USP Dissolution Test 1. Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the partially scored side) Bottles of 100.........................................................................................NDC 0083-0027-30 Bottles of 1000.......................................................................................NDC 0083-0027-40 Unit Dose (blister pack) Box of 100 (strips of 10)..................................................................NDC 0083-0027-32 Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP). Meets USP Dissolution Test 2. XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on one side Bottles of 100.........................................................................................NDC 0083-0061-30 XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on one side Bottles of 100.........................................................................................NDC 0083-0062-30 XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on one side Bottles of 100.........................................................................................NDC 0083-0060-30 Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture. Dispense in tight, container (USP). Suspension 100 mg/5 mL (teaspoon) - yellow-orange, citrus-vanilla flavored Bottles of 450 mL..................................................................................NDC 0083-0019-76 Shake well before using. Do not store above 30°C (86°F). Dispense in tight, light resistant container (USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tegretol Chewable Tablets Manufactured by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Tegretol Tablets Manufactured by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Tegretol Suspension Manufactured by: Patheon Whitby Inc.Whitby Operations Whitby Ontario, Canada L1N 5Z5 Tegretol XR Tablets Manufactured by: Novartis Pharma GmbH D-79664 Wehr, Germany Manufactured for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 December 2007 © 2007 Novartis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:00.575278	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016608s098lbl.pdf', 'application_number': 16608, 'submission_type': 'SUPPL ', 'submission_number': 98}
10,897	NAVANE® Thiothixene Capsules Thiothixene Hydrochloride Concentrate WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis— Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug- treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Navane is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Navane® (thiothixene) is a thioxanthene derivative. Specifically, it is the cis isomer of N,N dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene] thioxanthene-2-sulfonamide. Chemical St r uc ture The thioxanthenes differ from the phenothiazines by the replacement of nitrogen in the central ring with a carbon-linked side chain fixed in space in a rigid structural configuration. An N,N dimethyl sulfonamide functional group is bonded to the thioxanthene nucleus. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inert ingredients for the capsule formulations are: hard gelatin capsules (which contain gelatin and titanium dioxide; may contain Yellow 10, Yellow 6, Blue 1, Green 3, Red 3, and other inert ingredients); lactose; magnesium stearate; sodium lauryl sulfate; starch. Inert ingredients for the oral concentrate formulation are: alcohol; cherry flavor; dextrose; passion fruit flavor; sorbitol solution; water. ACTIONS Navane is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. INDICATIONS Navane is effective in the management of schizophrenia. Navane has not been evaluated in the management of behavioral complications in patients with mental retardation. CONTRAINDICATIONS Navane is contraindicated in patients with circulatory collapse, comatose states, central nervous system depression due to any cause, and blood dyscrasias. Navane is contraindicated in individuals who have shown hypersensitivity to the drug. It is not known whether there is a cross sensitivity between the thioxanthenes and the phenothiazine derivatives, but this possibility should be considered. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis— Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Navane is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Tardive Dyskinesia–Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene(1). Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to “Information for Patients” in the PRECAUTIONS section, and to the ADVERSE REACTIONS section.) Neuroleptic Malignant Syndrome (NMS)–A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene(2). Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usage in Pregnancy–Safe use of Navane during pregnancy has not been established. Therefore, this drug should be given to pregnant patients only when, in the judgment of the physician, the expected benefits from the treatment exceed the possible risks to mother and fetus. Animal reproduction studies and clinical experience to date have not demonstrated any teratogenic effects. In the animal reproduction studies with Navane, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. Similar findings have been reported with other psychotropic agents. After repeated oral administration of Navane to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen. Usage in Children–The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. As is true with many CNS drugs, Navane may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, especially during the first few days of therapy. Therefore, the patient should be cautioned accordingly. As in the case of other CNS-acting drugs, patients receiving Navane (thiothixene) should be cautioned about the possible additive effects (which may include hypotension) with CNS depressants and with alcohol. PRECAUTIONS An antiemetic effect was observed in animal studies with Navane; since this effect may also occur in man, it is possible that Navane may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor. In consideration of the known capability of Navane and certain other psychotropic drugs to precipitate convulsions, extreme caution should be used in patients with a history of convulsive disorders or those in a state of alcohol withdrawal, since it may lower the convulsive threshold. Although Navane potentiates the actions of the barbiturates, the dosage of the anticonvulsant therapy should not be reduced when Navane is administered concurrently. Though exhibiting rather weak anticholinergic properties, Navane should be used with caution in patients who might be exposed to extreme heat or who are receiving atropine or related drugs. Use with caution in patients with cardiovascular disease. Caution as well as careful adjustment of the dosages is indicated when Navane is used in conjunction with other CNS depressants. Also, careful observation should be made for pigmentary retinopathy and lenticular pigmentation (fine lenticular pigmentation has been noted in a small number of patients treated with Navane 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda for prolonged periods). Blood dyscrasias (agranulocytosis, pancytopenia, thrombocytopenic purpura), and liver damage (jaundice, biliary stasis) have been reported with related drugs. Antipsychotic drugs, including thiothixene(3), elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. Information for Patients: Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. Drug Interactions: Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness.(4,5) Due to a possible additive effect with hypotensive agents, patients receiving these drugs should be observed closely for signs of excessive hypotension when thiothixene is added to their drug regimen.(6) ADVERSE REACTIONS NOTE: Not all of the following adverse reactions have been reported with Navane. However, since Navane has certain chemical and pharmacologic similarities to the phenothiazines, all of the known side effects and toxicity associated with phenothiazine therapy should be borne in mind when Navane is used. Cardiovascular Effects: Tachycardia, hypotension, lightheadedness, and syncope. In the event hypotension occurs, epinephrine should not be used as a pressor agent since a paradoxical further lowering of blood pressure may result. Nonspecific EKG changes have been observed in some patients receiving Navane. These changes are usually reversible and frequently disappear on continued Navane therapy. The incidence of these changes is lower than that observed with some phenothiazines. The clinical significance of these changes is not known. CNS Effects: Drowsiness, usually mild, may occur although it usually subsides with continuation of Navane therapy. The incidence of sedation appears similar to that of the 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda piperazine group of phenothiazines but less than that of certain aliphatic phenothiazines. Restlessness, agitation and insomnia have been noted with Navane. Seizures and paradoxical exacerbation of psychotic symptoms have occurred with Navane infrequently. Hyperreflexia has been reported in infants delivered from mothers having received structurally related drugs. In addition, phenothiazine derivatives have been associated with cerebral edema and cerebrospinal fluid abnormalities. Extrapyramidal Symptoms Extrapyramidal symptoms, such as pseudoparkinsonism, akathisia and dystonia have been reported (see Dystonia, Class effect). Management of these extra-pyramidal symptoms depends upon the type and severity. Rapid relief of acute symptoms may require the use of an injectable antiparkinson agent. More slowly emerging symptoms may be managed by reducing the dosage of Navane and/or administering an oral antiparkinson agent. Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Persistent Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy with thiothixene(1) or may occur after drug therapy has been discontinued. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities. Since early detection of tardive dyskinesia is important, patients should be monitored on an ongoing basis. It has been reported that fine vermicular movement of the tongue may be an early sign of the syndrome. If this or any other presentation of the syndrome is observed, the clinician should consider possible discontinuation of antipsychotic medication. (See WARNINGS section.) Hepatic Effects: Elevations of serum transaminase and alkaline phosphatase, usually transient, have been infrequently observed in some patients. No clinically confirmed cases of jaundice attributable to Navane (thiothixene) have been reported. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hematologic Effects: As is true with certain other psychotropic drugs, leukopenia and leucocytosis, which are usually transient, can occur occasionally with Navane. Other antipsychotic drugs have been associated with agranulocytosis, eosinophilia, hemolytic anemia, thrombocytopenia and pancytopenia. Allergic Reactions: Rash, pruritus, urticaria, photosensitivity and rare cases of anaphylaxis have been reported with Navane. Undue exposure to sunlight should be avoided. Although not experienced with Navane, exfoliative dermatitis and contact dermatitis (in nursing personnel) have been reported with certain phenothiazines. Endocrine/Reproductive: Hyperprolactinemia(3); lactation, menstrual irregularities, moderate breast enlargement and amenorrhea have occurred in a small percentage of females receiving Navane. If persistent, this may necessitate a reduction in dosage or the discontinuation of therapy. Phenothiazines have been associated with false positive pregnancy tests, gynecomastia, hypoglycemia, hyperglycemia and glycosuria. Autonomic Effects: Dry mouth, blurred vision, nasal congestion, constipation, increased sweating, increased salivation and impotence have occurred infrequently with Navane therapy. Phenothiazines have been associated with miosis, mydriasis, and adynamic ileus. Other Adverse Reactions: Hyperpyrexia, anorexia, nausea, vomiting, diarrhea, increase in appetite and weight, weakness or fatigue, polydipsia, and peripheral edema. Although not reported with Navane, evidence indicates there is a relationship between phenothiazine therapy and the occurrence of a systemic lupus erythematosus-like syndrome. Neuroleptic Malignant Syndrome (NMS): Please refer to the text regarding NMS in the WARNINGS section. NOTE: Sudden deaths have occasionally been reported in patients who have received certain phenothiazine derivatives. In some cases the cause of death was apparently cardiac arrest or asphyxia due to failure of the cough reflex. In others, the cause could not be determined nor could it be established that death was due to phenothiazine administration. DOSAGE AND ADMINISTRATION Dosage of Navane should be individually adjusted depending on the chronicity and severity of the symptoms of schizophrenia. In general, small doses should be used initially and gradually increased to the optimal effective level, based on patient response. Some patients have been successfully maintained on once-a-day Navane therapy. The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In milder conditions, an initial dose of 2 mg three times daily is recommended. If indicated, a subsequent increase to 15 mg/day total daily dose is often effective. In more severe conditions, an initial dose of 5 mg twice daily is recommended. The usual optimal dose is 20 to 30 mg daily. If indicated, an increase to 60 mg/day total daily dose is often effective. Exceeding a total daily dose of 60 mg rarely increases the beneficial response. OVERDOSAGE Manifestations include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma. Treatment: Essentially symptomatic and supportive. Early gastric lavage is helpful. Keep patient under careful observation and maintain an open airway, since involvement of the extrapyramidal system may produce dysphagia and respiratory difficulty in severe overdosage. If hypotension occurs, the standard measures for managing circulatory shock should be used (I.V. fluids and/or vasoconstrictors). If a vasoconstrictor is needed, levarterenol and phenylephrine are the most suitable drugs. Other pressor agents, including epinephrine, are not recommended, since phenothiazine derivatives may reverse the usual pressor action of these agents and cause further lowering of blood pressure. If CNS depression is marked, symptomatic treatment is indicated. Extrapyramidal symptoms may be treated with antiparkinson drugs. There are no data on the use of peritoneal or hemodialysis, but they are known to be of little value in phenothiazine intoxication. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Navane (thiothixene) Capsules Bottles of 100’s: 1 mg (NDC 0049-5710-66) 2 mg (NDC 0049-5720-66) 5 mg (NDC 0049-5730-66) 10 mg (NDC 0049-5740-66) 20 mg (NDC 0049-5770-66) Rx only pfizer logo LAB-0251-6.0 Revised June 2008 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:00.614584	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/016584s058lbl.pdf', 'application_number': 16584, 'submission_type': 'SUPPL ', 'submission_number': 58}
10,893	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SODIUM IODIDE I 131 CAPSULES THERAPEUTIC safely and effectively. See full prescribing information for SODIUM IODIDE I 131 CAPSULES THERAPEUTIC. SODIUM IODIDE I 131 CAPSULES THERAPEUTIC for oral use Initial U.S. Approval: 1971 ---------------------------RECENT MAJOR CHANGES --------------------------- Contraindications (4) 03/2014 ----------------------------INDICATIONS AND USAGE --------------------------- Sodium Iodide I 131 Capsules Therapeutic is a radioactive therapeutic agent indicated for the treatment of hyperthyroidism and thyroid carcinomas that take up iodine. Palliative effects may be observed in patients with advanced thyroid malignancy if the metastatic lesions take up iodine. (1) ----------------------- DOSAGE AND ADMINISTRATION ---------------------- Use safe handling measures to minimize inadvertent radiation exposure. (2.1) Hyperthyroidism • 148 to 370 megabecquerels (MBq) (4 to 10 millicuries, mCi). Toxic nodular goiter and other situations may require larger doses. (2.2) Thyroid Carcinoma • For thyroid carcinoma, 3700 to 5550 MBq (100 to 150 mCi). (2.3) • For post-operative ablation of normal thyroid tissue: 1850 MBq (50 mCi). (2.3) Individualize therapy, including dose selection, based upon patient- specific factors detected during the therapeutic planning process. (2.4) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Capsules: available in 18 strengths from 0.75 mCi to 100 mCi at the time of calibration. See full prescribing information for details. (3) -------------------------------CONTRAINDICATIONS ------------------------------ • Patients with vomiting and diarrhea (4) • Treatment of thyroid malignancies shown to have no iodide uptake (4) • Pregnancy (4) • Breastfeeding (4) ----------------------- WARNINGS AND PRECAUTIONS----------------------- • Radiation-induced thyroiditis: may cause or worsen hyperthyroidism; consider pre-treatment with anti-thyroid medications. (5.1) • Thyroid enlargement, including that due to thyroid stimulating hormone concomitant therapy, may obstruct structures in the neck. Evaluate patients at high risk. (5.2) • Multiple non-thyroid radiation toxicities have been reported following sodium iodide I-131 therapy, including increased risks for neoplasia, hematopoietic suppression, and fetal or reproductive toxicity. Individualize dosage, verify absence of pregnancy, monitor patients for toxicity, and advise patients on contraceptive use. (5.3, 5.5, 5.6) ------------------------------ ADVERSE REACTIONS ----------------------------- • Adverse reactions that have been reported with doses of sodium iodide I-131 used in the treatment of benign disease include sialadenitis, chest pain, tachycardia, iododerma, itching skin, rash, hives, hypothyroidism, hyperthyroidism, thyrotoxic crisis, hypoparathyroidism, and local swelling. (6) • Adverse reactions that have been reported with doses of sodium iodide I-131 used in the treatment of malignant disease include radiation sickness, bone marrow depression, anemia, leucopenia, thrombocytopenia, blood dyscrasia, leukemia, solid cancers, lacrimal gland dysfunction, salivary gland dysfunction, congenital hypothyroidism, and chromosomal abnormalities. (6) To report SUSPECTED ADVERSE REACTIONS contact Mallinckrodt Inc. at 1-888-744-1414 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------------------------------DRUG INTERACTIONS ------------------------------ Many pharmacologic agents are known to interact with radioiodide. See full prescribing information complete list. (7) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Nursing Mothers: to minimize the absorbed radiation dose to breast tissue, discontinue breastfeeding at least four weeks before sodium iodide I-131 therapy. If administered in the postpartum period, the lactating mother should not breast-feed. (8.3) • Pediatric Use: safety and effectiveness in pediatric patients have not been established. (8.4) • Geriatric Use: enhanced evaluation, dose selection and follow-up procedures may be necessary for geriatric patients due to underlying co-morbidities, including renal dysfunction. (8.5) • Renal Impairment: may increase radiation exposure. (8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised 03/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Radiation Safety 2.2 Hyperthyroidism 2.3 Thyroid Carcinoma 2.4 Individualization of Therapy 2.5 Radiation Dosimetry 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Radiation-induced Thyroiditis 5.2 Thyroid-stimulating Hormone (TSH) and Thyroid Enlargement 5.3 Radiation-induced Toxicities 5.4 Hypersensitivity Reactions 5.5 Fetal Risk 5.6 Transient Infertility 5.7 Radiation Exposure Risk to Other Individuals 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 11.1 Physical Characteristics 11.2 External Radiation 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. 03_2014.2 Page 1 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Sodium Iodide I 131 Capsules Therapeutic is indicated for the treatment of hyperthyroidism and thyroid carcinomas that take up iodide. Palliative effects may be observed in patients with advanced thyroid malignancy if the metastatic lesions take up iodide. 2 DOSAGE AND ADMINISTRATION 2.1 Radiation Safety Sodium iodide I-131 capsules emit radiation and must be handled with safety measures to minimize inadvertent radiation exposure to clinical personnel and patients [see Warnings and Precautions (5.7)]. • Radiopharmaceuticals should be used only by or under the direction of physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. • Wear waterproof gloves during the entire sodium iodide I-131 capsule handling and administration procedure. • Maintain adequate shielding during the radiation-emitting life of the product. • Measure the patient dose using a suitable radioactivity calibration system immediately prior to administration. 2.2 Hyperthyroidism For hyperthyroidism, the usual sodium iodide I-131 dose range is 148 to 370 MBq (4 to 10 mCi). Higher doses may be necessary for the treatment of toxic nodular goiter and other special situations. Consider discontinuation of anti-thyroid therapy in a severely hyperthyroid patient three to four days before administration of sodium iodide I-131. Evaluate patients for risk of thyroid enlargement and obstruction of structures in the neck [see Warnings and Precautions (5.1, 5.2)]. 2.3 Thyroid Carcinoma For thyroid carcinoma, the usual sodium iodide I-131 therapeutic dose is 3700 to 5550 MBq (100 to 150 mCi). For ablation of post-operative residual thyroid tissue, the usual dose is 1850 MBq (50 mCi). 2.4 Individualization of Therapy Individualize sodium iodide I-131 therapy, including dose selection, based upon patient- specific factors such as the nature of the underlying condition, co-morbidities, age, estimated thyroid tissue iodine uptake, thyroid size, as well as ability of the patient to comply with the therapeutic regimen and radiation safety procedures. Perform a clinical assessment, including history, physical examination and laboratory testing when preparing patients for sodium iodide I-131 therapy in order to detect conditions which 03_2014.2 Page 2 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda may alter thyroid iodine uptake and increase the risks of the therapy or diminish its effectiveness. For example, intake of iodine in radiographic contrast may diminish thyroid iodine uptake while low serum chloride or nephrosis may increase thyroid iodine uptake. Obtain a drug history and ascertain whether any medications need to be withheld before the administration of the therapy [see Drug Interactions (7)]. 2.5 Radiation Dosimetry The estimated absorbed radiation doses1 to an average (70 kg) euthyroid (normal functioning thyroid) patient from an oral dose of iodine-131 in both milligray (mGy) per megabecquerel (MBq) and rad per millicurie (mCi) are shown in Table 1. Table 1. Absorbed Radiation Doses Tissue Thyroid Uptake 5% 15% 25% mGy/ MBq rads/ mCi mGy/ MBq rads/ mCi mGy/ MBq rads/ mCi Thyroid Stomach Wall Red Marrow Liver Testes Ovaries Urinary Bladder Salivary Glands2 Other 72 0.45 0.038 0.03 0.029 0.044 0.58 0.5 0.040 266 1.7 0.14 0.11 0.11 0.16 2.1 1.85 0.15 210 0.46 0.054 0.032 0.028 0.043 0.52 0.5 0.065 777 1.7 0.20 0.12 0.10 0.16 1.9 1.85 0.24 360 0.46 0.07 0.035 0.027 0.043 0.46 0.5 0.090 1300 1.7 0.26 0.13 0.10 0.16 1.7 1.85 0.33 3 DOSAGE FORMS AND STRENGTHS Sodium Iodide I 131 Capsules Therapeutic are opaque white capsules supplied in multiple strengths (Table 2). 03_2014.2 Page 3 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2. Capsule Strengths Strengths Available Total Radioactivity per Capsule (* At time of calibration) 28 MBq (0.75 mCi) 74 MBq (2 mCi) 111 MBq (3 mCi) 148 MBq (4 mCi) 185 MBq (5 mCi) 222 MBq (6 mCi) 259 MBq (7 mCi) 296 MBq (8 mCi) 370 MBq (10 mCi) 444 MBq (12 mCi) 555 MBq (15 mCi) 629 MBq (17 mCi) 740 MBq (20 mCi) 1850 MBq (50 mCi) 3700 MBq (100 mCi) 4 CONTRAINDICATIONS Sodium Iodide I 131 Capsules Therapeutic is contraindicated in: • Patients with vomiting and diarrhea [see Warnings and Precautions (5.7)]. • The treatment of thyroid malignancies shown to have no iodide uptake, which include the majority of medullary and anaplastic carcinomas. • Pregnancy [see Warnings and Precautions (5.5)]. • Breastfeeding [see Use in Specific Populations (8.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Radiation-induced Thyroiditis Sodium iodide I-131 may cause thyroiditis with gland enlargement and release of thyroid hormone, particularly when used to treat hyperthyroidism. The thyroiditis may cause or worsen hyperthyroidism, and may cause thyroid storm. When treating hyperthyroidism, consider pre-treatment with anti-thyroid medication to help deplete the thyroid hormone content within the gland. Discontinue the anti-thyroid medication at least three days before administration of sodium iodide I-131. Consider beta-blocker therapy before administration of sodium iodide I-131 to minimize the risk of hyperthyroidism and thyroid storm. 03_2014.2 Page 4 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.2 Thyroid-stimulating Hormone (TSH) and Thyroid Enlargement Enhanced TSH secretion, e.g., following discontinuation of anti-thyroid medications, or the administration of TSH to enhance sodium iodide I-131 uptake, may cause thyroid enlargement and obstructive complications of the trachea, esophagus, or blood vessels in the neck. Evaluate patients at high risk of obstructive complications before preparative treatments known to cause thyroid enlargement. 5.3 Radiation-induced Toxicities Radiation-induced toxicities, including dose-dependent fatalities, have been reported following sodium iodide I-131 therapy. Post-marketing reports have identified an increased risk for neoplasia, as well as risks for hematopoietic suppression. Salivary and lacrimal gland toxicity is relatively common and may manifest as conjunctivitis, xerophthalmia, epiphora, sialadenitis and xerostomia [see Adverse Reactions (6)]. 5.4 Hypersensitivity Reactions Hypersensitivity reactions, including rash and hives have been reported following administration of sodium iodide I-131. Sodium iodide I-131 capsules may contain sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. During the pre-therapy assessment, question patients about a history of hypersensitivity to sulfite [see Adverse Reactions (6)]. 5.5 Fetal Risk Transplacental passage of sodium iodide I-131 can cause severe and possibly irreversible hypothyroidism in neonates [see Contraindications (4)]. Females and Males of Childbearing Potential When planning sodium iodide I-131 therapy for women of childbearing potential, obtain a pregnancy test and verify the absence of a pregnancy before initiating treatment. Advise women and men of childbearing potential to use two effective methods of contraception to avoid pregnancy for at least six months after sodium iodide I-131 administration. Advise patients of the potential need to use two effective methods of contraception to avoid pregnancy for an even longer period of time (e.g., one year) if additional sodium iodide I-131 therapy or radionuclide imaging is anticipated. 5.6 Transient Infertility Transient, dose-related impairment of testicular function has been reported after sodium iodide I-131 therapy. Consider sperm banking for men who are anticipated to receive a high cumulative sodium iodide I-131 dose (e.g., greater than 14 GBq). In females, transient ovarian failure has been observed after sodium iodide I-131 therapy. 03_2014.2 Page 5 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.7 Radiation Exposure Risk to Other Individuals Unwanted radiation exposure can occur from handling and administration of radiopharmaceuticals or from contaminated waste products, including urine and feces. Follow safe administration instructions to minimize unnecessary radiation exposure to patients and health care workers [see Dosage and Administration (2.1)]. Instruct patients on how to reduce unnecessary radiation exposure to others, especially family members following treatment. Review the most recent professional society guidelines and publications that describe the procedures for the safe use of sodium iodide I-131 therapy to minimize radiation toxicity risks to patients, radiation exposure risks to other individuals, and environmental radiation contamination risks. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: • Radiation-induced Thyroiditis [see Warnings and Precautions (5.1)] • Thyroid-stimulating Hormone and Thyroid Enlargement [see Warnings and Precautions (5.2)] • Radiation-induced Toxicities [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions [see Warnings and Precautions (5.4)] • Fetal Risk [see Warnings and Precautions (5.5)] • Transient Infertility [see Warnings and Precautions (5.6)] • Radiation Exposure to Other Individuals [see Warnings and Precautions (5.7)] Radiation-related adverse reactions are a function of the dose level received by the patient. The following adverse reactions have been reported with doses of sodium iodide I-131 used in the treatment of benign disease, such as hyperthyroidism: • Gastrointestinal disorders: sialadenitis • Cardiac disorders: chest pain and tachycardia • Skin and subcutaneous tissue disorders: iododerma, itching skin, rash, and hives • Endocrine disorders: hypothyroidism, hyperthyroidism, thyrotoxic crisis, hypoparathyroidism • General disorders and administration site conditions: local swelling The following adverse reactions have been reported with doses of sodium iodide I-131 used in the treatment of malignant disease: 03_2014.2 Page 6 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Blood and lymphatic system disorders including fatalities: radiation sickness, bone marrow depression, anemia, leucopenia, thrombocytopenia, and blood dyscrasia • Neoplasms benign, malignant and unspecified (including cysts and polyps): leukemia and solid cancers • Eye disorders: lacrimal gland dysfunction • Gastrointestinal disorders: salivary gland dysfunction, nausea, vomiting • Congenital, familial and genetic disorders: congenital hypothyroidism and chromosomal abnormalities Adverse reactions that occur after treatment of benign disease may also occur after treatment of malignant disease. Tenderness, pain on swallowing, sore throat, and cough have been reported, generally around the third day after sodium iodide I-131 administration. 7 DRUG INTERACTIONS Many pharmacologic agents interact with sodium iodide I-131. These agents may affect the iodide protein binding and alter the iodide pharmacokinetics and pharmacodynamics. Table 3. Drug Interactions Substance Average Duration of Effect Anti-thyroid drugs e.g., carbimazole, propylthiouracil 5 days Natural or synthetic thyroid hormone e.g., thyroxine tri-iodothyronine 4 weeks 2 weeks Iodine-containing medications e.g., amiodarone expectorants, vitamins 4 weeks 2 weeks Topical iodide 1-9 months X-ray contrast agents iodine-containing agents Up to 1 year Other drugs anticoagulants, antihistamines corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium 1 week 1 week 1 week 1-2 weeks 4 weeks 03_2014.2 Page 7 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Warnings and Precautions (5.5)]. 8.3 Nursing Mothers Sodium iodide I-131 is excreted into human milk and may reach concentrations equal to or greater than concentrations in maternal plasma. To minimize the absorbed radiation dose to the breast tissue, breastfeeding and breast-pumping should be discontinued for at least four weeks before administration of sodium iodide I-131. Sodium iodide I-131 is contraindicated in pregnancy; if sodium iodide I-131 is administered in the postpartum period, the lactating mother should not breast-feed the infant. Breastfeeding may resume with the birth of another child, if the mother does not receive sodium iodide I-131 during that postpartum period. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Published reports suggest that the thyroid gland of pediatric patients is more sensitive to the effects of sodium iodide I-131; however, it is unknown if the I-131 dose-response relationship is similar to that of adults. When considering the use of sodium iodide I-131 in pediatric patients, the risks, particularly carcinogenic risks, and benefits of sodium iodide I-131 must be carefully weighed against those of other possible treatments. 8.5 Geriatric Use Because elderly patients are more likely to have decreased renal function and co morbid conditions, enhanced evaluation, dose-selection consideration and follow-up may be necessary for elderly patients receiving sodium iodide I-131 therapy, compared to younger patients [see Use in Specific Populations (8.6)]. When treating hyperthyroidism in geriatric patients at risk of developing cardiac complications, pre-treatment and post-treatment with anti-thyroid drugs and/or beta- blockers may help minimize the risk of excessive post-treatment hyperthyroidism due to radiation-induced thyroiditis [see Warnings and Precautions (5.1)]. 8.6 Renal Impairment Sodium iodide I-131 is eliminated predominantly through renal clearance. Patients with renal impairment are subject to decreased excretion of sodium iodide I-131 and increased radiation exposure. Evaluate renal function for therapeutic planning [see Dosage and Administration (2.4)]. Sodium iodide I-131 is dialyzable. Hemodialysis can be used to reduce total body radiation exposure. 10 OVERDOSAGE In case of exposure to a radioactive dose of sodium iodide I-131 exceeding the intended therapeutic dose provide general supportive care, monitor for bone marrow and thyroid suppression and consider administering a thyroid blocking agent such as potassium iodide (KI) or perchlorate promptly within 4 to 6 hours after the exposure. Thyroid 03_2014.2 Page 8 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda blockade may reduce radiation exposure of thyroid tissue but would not prevent radiation injury to the rest of the body. Assess the benefit of administering a blocking agent against the risk of failure of sodium iodide I-131 therapy. 11 DESCRIPTION Sodium Iodide I 131 (Na I-131) Capsules Therapeutic is supplied for oral administration in opaque white gelatin capsules. The capsules are available in strengths ranging from 28 to 3700 MBq (0.75 to 100 mCi) iodine-131 at the time of calibration. Sodium iodide I-131 capsules are packaged in shielded, plastic vials containing one capsule per vial. Sodium iodide I-131 capsules are prepared by absorbing a solution of carrier-free sodium iodide I-131 that may contain sodium bisulfite into inert filler. The iodine-131 utilized in the preparation of the capsules contains not less than 99% iodine-131 at the time of calibration. The expiration date is not later than one month after the calibration date. The calibration date and the expiration date are stated on the label. 11.1 Physical Characteristics Iodine-131 decays by beta emission and associated gamma emission with a physical half-life of 8.02 days3. The principal beta emissions and gamma photons are listed in Table 4. Table 4. Principal Radiation Emission Data Mean Percent Radiation Per Energy (keV) Disintegration Beta-1 2.10 69.4 Avg. Beta-3 7.27 96.6 Avg. Beta-4 89.9 191.6 Avg. Gamma-7 6.14 284.3 Gamma-14 81.7 364.5 Gamma-17 7.17 637.0 11.2 External Radiation The specific gamma ray constant for iodine-131 is 2.20 R/hr-mCi at 1 cm. The first half- value thickness of lead (Pb) for iodine-131 is 0.27 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 5. For example, the use of 4.5 cm of Pb will decrease the external radiation exposure by a factor of about 1,000. 03_2014.2 Page 9 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 5. Radiation Attenuation by Lead Shielding4 Shield Thickness (Pb), cm Coefficient of Attenuation 0.27 0.99 2.6 4.5 0.5 10-1 10-2 10-3 To correct for physical decay of this radionuclide, the fractions that remain at selected time intervals after the date of calibration are shown in Table 6. Table 6. Physical Decay Chart Iodine-131: Half-Life 8.02 Days Days Fraction Remaining Days Fraction Remaining Days Fraction Remaining 0* 1 2 3 4 5 6 7 8 9 10 1.000 0.917 0.841 0.772 0.708 0.649 0.595 0.546 0.501 0.459 0.421 11 12 13 14 15 16 17 18 19 20 21 0.387 0.355 0.325 0.298 0.274 0.251 0.230 0.211 0.194 0.178 0.163 22 23 24 25 26 27 28 29 30 0.149 0.137 0.126 0.115 0.106 0.097 0.089 0.082 0.075 *Calibration Day 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Taken orally, sodium iodide I-131 is rapidly absorbed and distributed within the extracellular fluid of the body. The iodide is concentrated in the thyroid via the sodium/iodide symporter, and subsequently oxidized to iodine. The destruction of thyroidal tissue is achieved by the beta emission of sodium iodide I-131. 12.2 Pharmacodynamics The therapeutic effects of sodium iodide I-131 are a result of the ionizing radiation absorbed by the thyroidal tissue. Tissue damage is the result of direct insult to molecules by ionization and excitation and the consequent dissociation of those molecules. About 90% of local irradiation from sodium iodide I-131 is the result of beta radiation and 10% is the result of gamma radiation. 03_2014.2 Page 10 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12.3 Pharmacokinetics After oral administration, sodium iodide I-131 is absorbed rapidly from the upper gastrointestinal tract (90% in 60 minutes). The pharmacokinetics follow that of unlabelled iodide. After entering the blood stream, the iodide is distributed into the extra thyroidal compartment. From here it is predominantly taken up by the thyroid or excreted renally. In the thyroid, the trapped iodide is oxidized to iodine and organified. The sodium/iodide symporter (NIS) is responsible for the concentration of iodide in the thyroid. This active transport process concentrates iodide 20 to 40 times the plasma concentration under normal circumstances, and this may increase tenfold in the hyperthyroid state. NIS also mediates active iodide transport in other tissues, including salivary glands, nasolacrimal duct, lacrimal sac, gastric mucosa, lactating mammary gland, and the choroid plexus. The non-thyroidal iodide transporting tissues do not have the ability to organify accumulated iodide. Depending on renal and thyroid gland function, urinary excretion is 37 to 75% of the administered dose, fecal excretion is about 10%, and excretion in sweat is almost negligible. 15 REFERENCES 1 International Commission on Radiological Protection. Radiation Dose to Patients from Radiopharmaceuticals. ICRP Publication 53, Pergamon Press, New York, NY, 1988. 2 L. Johansson, S. Leide-Svegborn, S. Matteson, B. Nosslin. Biokinetics of Iodide in Man: Refinement of Current ICRP Dosimetry Models. Cancer Biotherapy & Radiopharmaceuticals, 18(3): 445-450, 2003. 3 Stabin MG, da Luz CQPL. Decay Data for Internal and External Dose Assessment, Health Phys. 83(4):471-475, 2002. 4 Smith David S., Stabin, Michael G. Exposure Rate Constants and Lead Shielding Values for Over 1,100 Radionuclides, Health Physics. 102(3):271-291, March 2012. 16 HOW SUPPLIED/STORAGE AND HANDLING Sodium Iodide I 131 Capsules Therapeutic is supplied in a shielded, plastic vial containing one opaque white gelatin capsule per vial. The capsules are available in strengths ranging from 28 to 3700 MBq (0.75 to 100 mCi) iodine-131 at the time of calibration. The expiration date is not later than one month after the calibration date. The calibration date and the expiration date are stated on the label. Do not use the product after the expiration date. 03_2014.2 Page 11 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sodium Iodide I 131 Capsules for Therapeutic Use NDC mCi Capsule 0019-9452-75 0.75 0019-9452-02 2 0019-9452-03 3 0019-9452-04 4 0019-9452-05 5 0019-9452-06 6 0019-9452-07 7 0019-9452-08 8 0019-9452-10 10 0019-9452-12 12 0019-9452-15 15 0019-9452-17 17 0019-9452-20 20 0019-9452-50 50 0019-9452-00 100 Storage Store at a controlled room temperature of 20° to 25°C (68° to 77°F). Storage and disposal of Sodium Iodide I 131 Capsules Therapeutic should be controlled in a manner that is in compliance with the appropriate regulations of the government agency authorized to license the use of this radionuclide. The U.S. Nuclear Regulatory Commission has approved distribution of this radiopharmaceutical to persons licensed to use byproduct material listed in 10 CFR 35.300, and to persons who hold an equivalent license issued by an Agreement State. 17 PATIENT COUNSELING INFORMATION Review the most recent professional society guidelines and publications that describe important components of the patient counseling process. • Discuss the measures to minimize inadvertent radiation exposure to the patient, members of the patient’s household, the public, and the environment. • Advise females and males of reproductive potential of the need to use two effective methods of contraception to avoid pregnancy for at least 6 months after I-131 administration due to fetal risk. Advise patients of the potential need to use two effective methods of contraception to avoid pregnancy for an even longer period of time (e.g., one year) if additional sodium iodide I-131 therapy and further radionuclide imaging is anticipated. • Advise patients of the possibility of transient infertility and possible use of sperm banking for males of reproductive potential. 03_2014.2 Page 12 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Among lactating females, discuss the need to discontinue breastfeeding and pumping at least four weeks before administration of sodium iodide I-131. If sodium iodide I-131 is administered in the postpartum period, advise the lactating mother to not breastfeed her infant. Manufactured by: Mallinckrodt Inc. St. Louis, MO 63134 USA A452I0 Rev 03/2014 company logo 03_2014.2 Page 13 of 13 Reference ID: 3474105 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:00.940424	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016517s011lbl.pdf', 'application_number': 16517, 'submission_type': 'SUPPL ', 'submission_number': 11}
10,898	NDA 016608/S-097 NDA 018281/S-045 NDA 018927/S-038 NDA 020234/S-026 FDA Approved Labeling Text dated 8/28/2015 Page 1 Tegretol® carbamazepine USP Chewable Tablets of 100 mg - red-speckled, pink Tablets of 200 mg – pink Suspension of 100 mg/5 mL Tegretol®-XR (carbamazepine extended-release tablets) 100 mg, 200 mg, 400 mg Rx only Prescribing Information WARNINGS SERIOUS DERMATOLOGIC REACTIONS AND HLA-B1502 ALLELE SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS). APLASTIC ANEMIA AND AGRANULOCYTOSIS APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5 TO 8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA. ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL, Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS. BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS. Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential. DESCRIPTION Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and its structural formula is: structural formula Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200 mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200 mg tablets only). CLINICAL PHARMACOLOGY In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia. Mechanism of Action Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown. The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been established. Pharmacokinetics In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of conventional Tegretol tablets, and 3 to 12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine 10,11 epoxide. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol. The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10 to 15 years of age). The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated. INDICATIONS AND USAGE Epilepsy Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: 1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types. 2. Generalized tonic-clonic seizures (grand mal). 3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General). Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Trigeminal Neuralgia Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains. CONTRAINDICATIONS Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase (MAO) inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits. Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated. WARNINGS Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. SJS/TEN and HLA-B1502 Allele Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity. Across Asian populations, notable variation exists in the prevalence of HLA-B1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B1502, averaging 2% to 4%, but higher in some groups. HLA-B1502 is present in less than 1% of the population in Japan and Korea. HLA-B1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans). Prior to initiating Tegretol therapy, testing for HLA-B1502 should be performed in patients with ancestry in populations in which HLA-B1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients positive for HLA-B1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see BOXED WARNING and PRECAUTIONS, Laboratory Tests). Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on Tegretol. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The HLA-B1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Tegretol such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B1502 positive patients, when alternative therapies are otherwise equally acceptable. Hypersensitivity Reactions and HLA-A3101 Allele Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA A3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). HLA-A3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (for example, Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese, Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry. The risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to be positive for HLA-A3101. Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B1502-positive and HLA-A3101-positive patients treated with Tegretol will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B1502-negative and HLA-A3101-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring, have not been studied. Aplastic Anemia and Agranulocytosis Aplastic anemia and agranulocytosis have been reported in association with the use of TEGRETOL (see BOXED WARNING). Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with Tegretol. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Tegretol should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present, benefits and risks should be carefully considered and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully monitored. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should be informed that about a third of patients who have had hypersensitivity reactions to carbamazepine also experience hypersensitivity reactions with oxcarbazepine (Trileptal®). Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. General Tegretol has shown mild anticholinergic activity that may be associated with increased intraocular pressure; therefore, patients with increased intraocular pressure should be closely observed during therapy. Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind. The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria. As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased seizure frequency. Hyponatremia can occur as a result of treatment with Tegretol. In many cases, the hyponatremia appears to be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of developing SIADH with Tegretol treatment appears to be dose-related. Elderly patients and patients treated with diuretics are at greater risk of developing hyponatremia. Consider discontinuing Tegretol in patients with symptomatic hyponatremia. Signs and symptoms of hyponatremia include headache, new or increased seizure frequency, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Consider discontinuing Tegretol in patients with symptomatic hyponatremia. Usage in Pregnancy Carbamazepine can cause fetal harm when administered to a pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. When treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women. In humans, transplacental passage of carbamazepine is rapid (30 to 60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung. Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10 to 25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5 to 4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg. Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may represent a neonatal withdrawal syndrome. To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. PRECAUTIONS General Before initiating therapy, a detailed history and physical examination should be made. Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE). Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second- and third-degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol. AV heart block, including second- and third-degree block, have been reported following Tegretol treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances. Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug. In addition rare instances of vanishing bile duct syndrome have been reported. This syndrome consists of a cholestatic process with a variable clinical course ranging from fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts. Some, but not all, cases are associated with features that overlap with other immunoallergenic syndromes such as multiorgan hypersensitivity (DRESS syndrome) and serious dermatologic reactions. As an example there has been a report of vanishing bile duct syndrome associated with Stevens-Johnson syndrome and in another case an association with fever and eosinophilia. Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION). Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance. Information for Patients Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking Tegretol. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the event a skin reaction should occur while taking Tegretol, patients should consult with their physician immediately (see WARNINGS). Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription medications or herbal products. Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive sedative effect. Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks. Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection). Laboratory Tests For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B1502 typing’ is recommended. The test is positive if either one or two HLA-B1502 alleles are detected and negative if no HLA-B1502 alleles are detected. Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease. Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes. Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction. Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used. Thyroid function tests have been reported to show decreased values with Tegretol administered alone. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Interference with some pregnancy tests has been reported. Drug Interactions There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril®, resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION). Clinically meaningful drug interactions have occurred with concomitant medications and include (but are not limited to) the following: Agents That May Affect Tegretol Plasma Levels When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required. Agents That Increase Carbamazepine Levels CYP3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, and protease inhibitors. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Coadministration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations. Accordingly, the dosage of Tegretol should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid. Agents That Decrease Carbamazepine Levels CYP3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline. Effect of Tegretol on Plasma Levels of Concomitant Agents Decreased Levels of Concomitant Medications Tegretol is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with Tegretol, monitoring of concentrations or dosage adjustment of these agents may be necessary: • When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced. • When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered. • The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced. • Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS). • Monitor concentrations of valproate when Tegretol is introduced or withdrawn in patients using valproic acid. In addition, Tegretol causes, or would be expected to cause, decreased levels of the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary: acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide. Other Drug Interactions • Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic coadministration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine. • Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. • Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity. • Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications. • Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered. • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine. Whether or not carbamazepine has the same effect on other non- Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. Carcinogenesis, Mutagenesis, Impairment of Fertility Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males. Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown. Usage in Pregnancy Pregnancy Category D (see WARNINGS). Labor and Delivery The effect of Tegretol on human labor and delivery is unknown. Nursing Mothers Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to the newborn during breastfeeding are in the range of 2 to 5 mg daily for Tegretol and 1 to 2 mg daily for the epoxide. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children. Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e. 4 to 12 mcg/mL) is the same in children and adults. The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available. Geriatric Use No systematic studies in geriatric patients have been conducted. ADVERSE REACTIONS If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED WARNING), the liver, and the cardiovascular system. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended. The following additional adverse reactions have been reported: Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda. Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis, onychomadesis and hirsutism. In certain cases, discontinuation of therapy may be necessary. Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy. Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds. Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis, very rare cases of hepatic failure. Pancreatic: Pancreatitis. Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia. Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been rare reports of impaired male fertility and/or abnormal spermatogenesis. Testicular atrophy occurred in rats receiving Tegretol orally from 4 to 52 weeks at dosage levels of 50 to 400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown. Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome. There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs. Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis. Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure (see WARNINGS, General) as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes. Musculoskeletal System: Aching joints and muscles, and leg cramps. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolism: Fever and chills. Hyponatremia (seeWARNINGS,General). Decreased levels of plasma calcium have been reported. Osteoporosis has been reported. Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants. A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine. DRUG ABUSE AND DEPENDENCE No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or physical dependence in humans. OVERDOSAGE Acute Toxicity Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia). Oral LD50 in animals (mg/kg): mice, 1100 to 3750; rats, 3850 to 4025; rabbits, 1500 to 2680; guinea pigs, 920. Signs and Symptoms The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than 60 g) have been ingested. Respiration: Irregular breathing, respiratory depression. Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders. Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia. Gastrointestinal Tract: Nausea, vomiting. Kidneys and Bladder: Anuria or oliguria, urinary retention. Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias. Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified. Treatment The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote. Elimination of the Drug: Induction of vomiting. Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol. Measures to Reduce Absorption: Activated charcoal, laxatives. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Measures to Accelerate Elimination: Forced diuresis. Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children. Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen. Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered. Convulsions: Diazepam or barbiturates. Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week). Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days. Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery. Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels. A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought. DOSAGE AND ADMINISTRATION (SEE TABLE BELOW) Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medications or diluents. Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. Medication should be taken with meals. Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended to start with low doses (children 6 to 12 years: ½ teaspoon q.i.d.) and to increase slowly to avoid unwanted side effects. Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d. suspension). Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be noticeable in the stool. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Epilepsy (SEE INDICATIONS AND USAGE) Adults and children over 12 years of age-Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12 to 15 years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level, usually 800 to 1200 mg daily. Children 6 to 12 years of age-Initial: Either 100 mg b.i.d. for tablets or XR tablets, or ½ teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level, usually 400 to 800 mg daily. Children under 6 years of age-Initial: 10 to 20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be made. Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug Interactions, and Pregnancy Category D). Trigeminal Neuralgia (SEE INDICATIONS AND USAGE) Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or ½ teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (½ teaspoon) q.i.d. for suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in most patients with 400 to 800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage Information Initial Dose Subsequent Dose Maximum Daily Dose Indication Tablet* XR† Suspension Tablet* XR† Suspension Tablet* XR† Suspension Epilepsy Under 6 yr 10-20 mg/kg/day b.i.d. or t.i.d. 10-20 mg/kg/day q.i.d. Increase weekly to achieve optimal clinical response, t.i.d. or q.i.d. Increase weekly to achieve optimal clinical response, t.i.d. or q.i.d. 35 mg/kg/24 hr (see Dosage and Administration section above) 35 mg/kg/24 hr (see Dosage and Administration section above) 6-12 yr 100 mg b.i.d. (200 mg/day) 100 mg b.i.d. (200 mg/day) ½ tsp q.i.d. (200 mg/day) Add up to 100 mg/day at weekly intervals, t.i.d. or q.i.d. Add 100 mg/day at weekly intervals, b.i.d. Add up to 1 tsp (100 mg)/day at weekly intervals, t.i.d. or q.i.d. 1000 mg/24 hr Over 12 yr 200 mg b.i.d. 200 mg b.i.d. 1 tsp q.i.d. Add up to Add up to Add up to 2 tsp 1000 mg/24 hr (12-15 yr) (400 mg/day) (400 mg/day) (400 mg/day) 200 mg/day at 200 mg/day (200 mg)/day at 1200 mg/24 hr (>15 yr) weekly intervals, t.i.d. or q.i.d. at weekly intervals, b.i.d. weekly intervals, t.i.d. or q.i.d. 1600 mg/24 hr (adults, in rare instances) Trigeminal 100 mg b.i.d. 100 mg b.i.d. ½ tsp q.i.d. Add up to Add up to Add up to 2 tsp 1200 mg/24 hr Neuralgia (200 mg/day) (200 mg/day) (200 mg/day) 200 mg/day in increments of 100 mg every 12 hr 200 mg/day in increments of 100 mg every 12 hr (200 mg)/day in increments of 50 mg (½ tsp) q.i.d. Tablet = Chewable or conventional tablets †XR = Tegretol-XR extended-release tablets Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52 twice on the scored side) Bottles of 100 ............................................................................................................................ NDC 0078-0492-05 Unit Dose (blister pack) Box of 100 (strips of 10) ........................................................................................................... NDC 0078-0492-35 Do not store above 30°C (86°F). Protect from light and moisture. Dispense in tight, light-resistant container (USP). Meets USP Dissolution Test 1. Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the partially scored side) Bottles of 100 ............................................................................................................................ NDC 0078-0509-05 Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP). Meets USP Dissolution Test 2. XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on one side Bottles of 100 ............................................................................................................................ NDC 0078-0510-05 XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on one side Bottles of 100 ............................................................................................................................ NDC 0078-0511-05 XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on one side Bottles of 100 ............................................................................................................................ NDC 0078-0512-05 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) Protect from moisture. Dispense in tight container (USP). Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored Bottles of 450 mL ..................................................................................................................... NDC 0078-0508-83 Shake well before using. Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP). Thorazine® is a registered trademark of GlaxoSmithKline. September 2015 Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE TEGRETOL® and TEGRETOL®-XR (Teg-ret-ol) (carbamazepine) Tablets, Suspension, Chewable Tablets, Extended-Release Tablets Read this Medication Guide before you start taking Tegretol or Tegretol–XR (TEGRETOL) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about TEGRETOL? Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL suddenly can cause serious problems. TEGRETOL can cause serious side effects, including: 1. TEGRETOL may cause rare but serious skin rashes that may lead to death. These serious skin reactions are more likely to happen when you begin taking TEGRETOL within the first four months of treatment but may occur at later times. These reactions can happen in anyone, but are more likely in people of Asian descent. If you are of Asian descent, you may need a genetic blood test before you take TEGRETOL to see if you are at a higher risk for serious skin reactions with this medicine. Symptoms may include: • skin rash • hives • sores in your mouth • blistering or peeling of the skin 2. TEGRETOL may cause rare but serious blood problems. Symptoms may include: • fever, sore throat, or other infections that come and go or do not go away • easy bruising • red or purple spots on your body • bleeding gums or nose bleeds • severe fatigue or weakness 3. Like other antiepileptic drugs, TEGRETOL may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • new or worse depression • new or worse anxiety • feeling agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop TEGRETOL without first talking to a healthcare provider. Stopping TEGRETOL suddenly can cause serious problems. You should talk to your healthcare provider before stopping. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. What is TEGRETOL? TEGRETOL is a prescription medicine used to treat: • certain types of seizures (partial, tonic-clonic, mixed) • certain types of nerve pain (trigeminal and glossopharyngeal neuralgia) TEGRETOL is not a regular pain medicine and should not be used for aches or pains. Who should not take TEGRETOL? Do not take TEGRETOL if you: • have a history of bone marrow depression. • are allergic to carbamazepine or any of the ingredients in TEGRETOL. See the end of this Medication Guide for a complete list of ingredients in TEGRETOL. • take nefazodone. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. • have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. What should I tell my healthcare provider before taking TEGRETOL? Before you take TEGRETOL, tell your healthcare provider if you: • have or have had suicidal thoughts or actions, depression, or mood problems • have or ever had heart problems • have or ever had blood problems • have or ever had liver problems • have or ever had kidney problems • have or ever had allergic reactions to medicines • have or ever had increased pressure in your eye • have any other medical conditions • drink grapefruit juice or eat grapefruit • use birth control. TEGRETOL may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you take birth control and TEGRETOL. • are pregnant or plan to become pregnant. TEGRETOL may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking TEGRETOL. You and your healthcare provider should decide if you should take TEGRETOL while you are pregnant. ▪ If you become pregnant while taking TEGRETOL, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888 233-2334. • are breastfeeding or plan to breastfeed. TEGRETOL passes into breast milk. You and your healthcare provider should discuss whether you should take TEGRETOL or breastfeed; you should not do both. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking TEGRETOL with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take TEGRETOL? • Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy may cause seizures that will not stop (status epilepticus). • Take TEGRETOL exactly as prescribed. Your healthcare provider will tell you how much TEGRETOL to take. • Your healthcare provider may change your dose. Do not change your dose of TEGRETOL without talking to your healthcare provider. • Take TEGRETOL with food. • TEGRETOL-XR Tablets: • Do not crush, chew, or break TEGRETOL-XR tablets. • Tell your healthcare provider if you can not swallow TEGRETOL-XR whole. • TEGRETOL Suspension: • Shake the bottle well each time before use. • Do not take TEGRETOL suspension at the same time you take other liquid medicines. • If you take too much TEGRETOL, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking TEGRETOL? • Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TEGRETOL until you talk to your healthcare provider. TEGRETOL taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how TEGRETOL affects you. TEGRETOL may slow your thinking and motor skills. What are the possible side effects of TEGRETOL? See “What is the most important information I should know about TEGRETOL?” TEGRETOL may cause other serious side effects. These include: Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Irregular heartbeat - symptoms include: o Fast, slow, or pounding heartbeat o Shortness of breath o Feeling lightheaded o Fainting • Liver problems - symptoms include: o yellowing of your skin or the whites of your eyes o dark urine o pain on the right side of your stomach area (abdominal pain) o easy bruising o loss of appetite o nausea or vomiting Get medical help right away if you have any of the symptoms listed above or listed in “What is the most important information I should know about TEGRETOL?” The most common side effects of TEGRETOL include: • dizziness • drowsiness • problems with walking and coordination (unsteadiness) • nausea • vomiting These are not all the possible side effects of TEGRETOL. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store TEGRETOL? Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Do not store TEGRETOL Tablets above 30°C (86°F). • Keep TEGRETOL Tablets dry. • Do not store TEGRETOL Chewable Tablets above 30°C (86°F). • Keep TEGRETOL Chewable Tablets out of the light. • Keep TEGRETOL Chewable Tablets dry. • Store TEGRETOL-XR Tablets at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). • Keep TEGRETOL-XR Tablets dry. • Do not store TEGRETOL Suspension above 30°C (86°F). • Shake well before using. • Keep TEGRETOL Suspension in a tight, light-resistant container. Keep TEGRETOL and all medicines out of the reach of children. General Information about TEGRETOL Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TEGRETOL for a condition for which it was not prescribed. Do not give TEGRETOL to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about TEGRETOL. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for the full prescribing information about TEGRETOL that is written for health professionals. For more information, go to www.pharma.us.novartis.com or call 1-888-669-6682. What are the ingredients in TEGRETOL? Active ingredient: carbamazepine Inactive ingredients: • TEGRETOL Tablets: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200 mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). • TEGRETOL Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • TEGRETOL-XR Tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200 mg tablets only). This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis September 2015 Reference ID: 3812964 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:01.088099	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/016608s097,018281s045,018927s038,020234s026lbl.pdf', 'application_number': 16608, 'submission_type': 'SUPPL ', 'submission_number': 97}
10,901	company logo Tegretol® carbamazepine USP Chewable Tablets of 100 mg - red-speckled, pink Tablets of 200 mg – pink Suspension of 100 mg/5 mL Tegretol®-XR (carbamazepine extended-release tablets) 100 mg, 200 mg, 400 mg Rx only Prescribing Information WARNINGS SERIOUS DERMATOLOGIC REACTIONS AND HLA-B1502 ALLELE SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS). APLASTIC ANEMIA AND AGRANULOCYTOSIS APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA. ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS. Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential. DESCRIPTION Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and its structural formula is structural formula Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only). CLINICAL PHARMACOLOGY In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia. Mechanism of Action Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown. The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been established. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol. The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age). The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated. INDICATIONS AND USAGE Epilepsy Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: 1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types. 2. Generalized tonic-clonic seizures (grand mal). 3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General). Trigeminal Neuralgia Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits. Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated. WARNINGS Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. SJS/TEN and HLA-B1502 Allele Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity. Across Asian populations, notable variation exists in the prevalence of HLA-B1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B1502, averaging 2 to 4%, but higher in some groups. HLA-B1502 is present in <1% of the population in Japan and Korea. HLA-B1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans). Prior to initiating Tegretol therapy, testing for HLA-B1502 should be performed in patients with ancestry in populations in which HLA-B1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients positive for HLA-B1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS, Laboratory Tests). Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on Tegretol. The HLA-B1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]). Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda avoiding use of other drugs associated with SJS/TEN in HLA-B1502 positive patients, when alternative therapies are otherwise equally acceptable. Application of HLA-B1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B1502-positive Asian patients treated with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in HLA-B1502-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied. Aplastic Anemia and Agranulocytosis Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. General Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy. Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind. The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria. As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased seizure frequency. Usage in Pregnancy Carbamazepine can cause fetal harm when administered to a pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. In treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women. In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung. Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may represent a neonatal withdrawal syndrome. To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. PRECAUTIONS General Before initiating therapy, a detailed history and physical examination should be made. Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE). Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol. AV heart block, including second and third degree block, have been reported following Tegretol treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances. Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug. Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients). Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops. Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If positive, caution should be used in prescribing carbamazepine. In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal®). Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION). Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance. Information for Patients Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking Tegretol. Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the event a skin reaction should occur while taking Tegretol, patients should consult with their physician immediately (see WARNINGS). Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription medications or herbal products. Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive sedative effect. Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks. Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection). Laboratory Tests For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B1502 typing’ is recommended. The test is positive if either one or two HLA-B1502 alleles are detected and negative if no HLA-B1502 alleles are detected. Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes. Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction. Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used. Thyroid function tests have been reported to show decreased values with Tegretol administered alone. Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other drugs. Interference with some pregnancy tests has been reported. Drug Interactions There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine® solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION). Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following: Agents That May Affect Tegretol Plasma Levels CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include: cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, trazodone, loxapine, olanzapine, quetiapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, protease inhibitors, valproate. CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include: cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline. When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required. increased levels of the active 10,11-epoxide †decreased levels of carbamazepine and increased levels of the 10,11-epoxide Effect of Tegretol on Plasma Levels of Concomitant Agents Increased levels: clomipramine HCl, phenytoin, primidone Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of comedications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be expected to cause, decreased levels of the following: Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine), citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine, dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide. In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary. Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS). Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity. Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia. Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium). Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected. Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications. Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered. Carcinogenesis, Mutagenesis, Impairment of Fertility Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males. Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown. Usage in Pregnancy Pregnancy Category D (see WARNINGS). Labor and Delivery The effect of Tegretol on human labor and delivery is unknown. Nursing Mothers Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the epoxide. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children. Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults. The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available. Geriatric Use No systematic studies in geriatric patients have been conducted. ADVERSE REACTIONS If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED WARNING), the liver, and the cardiovascular system. The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the low dosage recommended. The following additional adverse reactions have been reported: Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda. Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear. Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy. Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds. Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure. Pancreatic: Pancreatitis. Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis. Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown. Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome. There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs. Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis. Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes. Musculoskeletal System: Aching joints and muscles, and leg cramps. Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium leading to osteoporosis have been reported. Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and abnormal liver function tests. These signs and symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and PRECAUTIONS, Information for Patients). Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants. A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine. DRUG ABUSE AND DEPENDENCE No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or physical dependence in humans. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE Acute Toxicity Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia). Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920. Signs and Symptoms The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (>60 g) have been ingested. Respiration: Irregular breathing, respiratory depression. Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders. Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia. Gastrointestinal Tract: Nausea, vomiting. Kidneys and Bladder: Anuria or oliguria, urinary retention. Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias. Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified. Treatment The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote. Elimination of the Drug: Induction of vomiting. Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol. Measures to Reduce Absorption: Activated charcoal, laxatives. Measures to Accelerate Elimination: Forced diuresis. Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children. Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen. Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered. Convulsions: Diazepam or barbiturates. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week). Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days. Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery. Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels. A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought. DOSAGE AND ADMINISTRATION (SEE TABLE BELOW) Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medications or diluents. Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. Medication should be taken with meals. Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase slowly to avoid unwanted side effects. Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d. suspension). Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be noticeable in the stool. Epilepsy (SEE INDICATIONS AND USAGE) Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level, usually 400-800 mg daily. Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be made. Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug Interactions, and Pregnancy Category D). Trigeminal Neuralgia (SEE INDICATIONS AND USAGE) Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage Information Initial Dose Subsequent Dose Maximum Daily Dose Indication Tablet* XR † Suspension Tablet* XR † Suspension Tablet* XR † Suspension Epilepsy Under 6 yr 10-20 mg/kg/day b.i.d. or t.i.d. 10-20 mg/kg/day q.i.d. Increase weekly to achieve optimal clinical response, t.i.d. or q.i.d. Increase weekly to achieve optimal clinical response, t.i.d. or q.i.d. 35 mg/kg/24 hr (see Dosage and Administration section above) 35 mg/kg/24 hr (see Dosage and Administration section above) 6-12 yr 100 mg b.i.d. (200 mg/day) 100 mg b.i.d. (200 mg/day) ½ tsp q.i.d. (200 mg/day) Add up to 100 mg/day at weekly intervals, t.i.d. or q.i.d. Add 100 mg/day at weekly intervals, b.i.d. Add up to 1 tsp (100 mg)/day at weekly intervals, t.i.d. or q.i.d. 1000 mg/24 hr Over 12 yr 200 mg b.i.d. 200 mg b.i.d. 1 tsp q.i.d. Add up to Add up to Add up to 2 tsp 1000 mg/24 hr (12-15 yr) (400 mg/day) (400 mg/day) (400 mg/day) 200 mg/day at 200 mg/day (200 mg)/day at 1200 mg/24 hr (>15 yr) weekly intervals, t.i.d. or q.i.d. at weekly intervals, b.i.d. weekly intervals, t.i.d. or q.i.d. 1600 mg/24 hr (adults, in rare instances) Trigeminal 100 mg b.i.d. 100 mg b.i.d. ½ tsp q.i.d. Add up to Add up to Add up to 2 tsp 1200 mg/24 hr Neuralgia (200 mg/day) (200 mg/day) (200 mg/day) 200 mg/day in increments of 100 mg every 12 hr 200 mg/day in increments of 100 mg every 12 hr (200 mg)/day in increments of 50 mg (½ tsp) q.i.d. Tablet = Chewable or conventional tablets †XR = Tegretol ®-XR extended-release tablets Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52 twice on the scored side) Bottles of 100............................................................................................................................ NDC 0078-0492-05 Unit Dose (blister pack) Box of 100 (strips of 10)........................................................................................................... NDC 0078-0492-35 Do not store above 30°C (86°F). Protect from light and moisture. Dispense in tight, light-resistant container (USP). Meets USP Dissolution Test 1. Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the partially scored side) Bottles of 100............................................................................................................................ NDC 0078-0509-05 Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP). Meets USP Dissolution Test 2. XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on one side Bottles of 100............................................................................................................................ NDC 0078-0510-05 XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on one side Bottles of 100............................................................................................................................ NDC 0078-0511-05 XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on one side Bottles of 100............................................................................................................................ NDC 0078-0512-05 Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture. Dispense in tight container (USP). Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored Bottles of 450 mL ..................................................................................................................... NDC 0078-0508-83 Shake well before using. Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP). Thorazine® is a registered trademark of GlaxoSmithKline. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 REV: AUGUST 2010 T2010-XX © Novartis Reference ID: 2912982 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:01.282719	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016608s100s102,018281s049s050,018927s041s042,020234s031s033lbl.pdf', 'application_number': 16608, 'submission_type': 'SUPPL ', 'submission_number': 102}
10,900	NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 1 Tegretol® carbamazepine USP Chewable Tablets of 100 mg - red-speckled, pink Tablets of 200 mg – pink Suspension of 100 mg/5 mL Tegretol®-XR (carbamazepine extended-release tablets) 100 mg, 200 mg, 400 mg Rx only Prescribing Information WARNINGS SERIOUS DERMATOLOGIC REACTIONS AND HLA-B1502 ALLELE SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS). APLASTIC ANEMIA AND AGRANULOCYTOSIS APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5 TO 8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 2 ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS. BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS. Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential. DESCRIPTION Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and its structural formula is: structural formula Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200 mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200 mg tablets only). Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 3 CLINICAL PHARMACOLOGY In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia. Mechanism of Action Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown. The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been established. Pharmacokinetics In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of conventional Tegretol tablets, and 3 to 12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine 10,11 epoxide. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 4 The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10 to 15 years of age). The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated. INDICATIONS AND USAGE Epilepsy Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: 1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types. 2. Generalized tonic-clonic seizures (grand mal). 3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General). Trigeminal Neuralgia Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains. CONTRAINDICATIONS Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase (MAO) inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits. Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 5 WARNINGS Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. SJS/TEN and HLA-B1502 Allele Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity. Across Asian populations, notable variation exists in the prevalence of HLA-B1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B1502, averaging 2 to 4%, but higher in some groups. HLA-B1502 is present in less than 1% of the population in Japan and Korea. HLA-B1502 is largely absent in individuals not of Asian origin (e.g. Caucasians, African-Americans, Hispanics, and Native Americans). Prior to initiating Tegretol therapy, testing for HLA-B1502 should be performed in patients with ancestry in populations in which HLA-B1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients positive for HLA-B1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see BOXED WARNING and PRECAUTIONS, Laboratory Tests). Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on Tegretol. The HLA-B1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Tegretol such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B1502 positive patients, when alternative therapies are otherwise equally acceptable. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 6 Hypersensitivity Reactions and HLA-A3101 Allele Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA A3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). HLA-A3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (for example, Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese, Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry. The risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to be positive for HLA-A3101. Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B1502-positive and HLA-A3101-positive patients treated with Tegretol will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B1502-negative and HLA-A3101-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring, have not been studied. Aplastic Anemia and Agranulocytosis Aplastic anemia and agranulocytosis have been reported in association with the use of TEGRETOL (see BOXED WARNING). Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with Tegretol. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Tegretol should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present, Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 7 benefits and risks should be carefully considered and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully monitored. In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may experience hypersensitivity reactions with oxcarbazepine (Trileptal®). Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 8 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. General Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy. Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind. The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria. As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased seizure frequency. Usage in Pregnancy Carbamazepine can cause fetal harm when administered to a pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g. craniofacial defects, cardiovascular malformations, hypospadias, and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. When treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 9 In humans, transplacental passage of carbamazepine is rapid (30 to 60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung. Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10 to 25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5 to 4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg. Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may represent a neonatal withdrawal syndrome. To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. PRECAUTIONS General Before initiating therapy, a detailed history and physical examination should be made. Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE). Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 10 AV heart block, including second and third degree block, have been reported following Tegretol treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances. Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug. In addition rare instances of vanishing bile duct syndrome have been reported. This syndrome consists of a cholestatic process with a variable clinical course ranging from fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts. Some, but not all, cases are associated with features that overlap with other immunoallergenic syndromes such as multiorgan hypersensitivity (DRESS syndrome) and serious dermatologic reactions. As an example there has been a report of vanishing bile duct syndrome associated with Stevens-Johnson syndrome and in another case an association with fever and eosinophilia. Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION). Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance. Information for Patients Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking Tegretol. Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the event a skin reaction should occur while taking Tegretol, patients should consult with their physician immediately (see WARNINGS). Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription medications or herbal products. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 11 Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive sedative effect. Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks. Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection). Laboratory Tests For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B1502 typing’ is recommended. The test is positive if either one or two HLA-B1502 alleles are detected and negative if no HLA-B1502 alleles are detected. Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease. Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes. Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction. Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used. Thyroid function tests have been reported to show decreased values with Tegretol administered alone. Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other drugs. Interference with some pregnancy tests has been reported. Drug Interactions There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 12 and liquid Mellaril®, resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION). Clinically meaningful drug interactions have occurred with concomitant medications and include (but are not limited to) the following: Agents That May Affect Tegretol Plasma Levels When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required. Agents That Increase Carbamazepine Levels CYP3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, and protease inhibitors. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations. Accordingly, the dosage of Tegretol should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid. Agents That Decrease Carbamazepine Levels CYP3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline. Effect of Tegretol on Plasma Levels of Concomitant Agents Decreased Levels of Concomitant Medications Tegretol is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with Tegretol, monitoring of concentrations or dosage adjustment of these agents may be necessary: • When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 13 • When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended. • The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered. • The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced. • Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS). • Monitor concentrations of valproate when tegretol is introduced or withdrawn in patients using valproic acid. In addition, tegretol causes, or would be expected to cause, decreased levels of the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary: acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide. Other Drug Interactions • Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic co-administration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine. • Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. • Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity. • Concomitant medication with Tegretol and some diuretics (e.g., hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia. • Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 14 • Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered. • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine. Whether or not carbamazepine has the same effect on other non depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. Carcinogenesis, Mutagenesis, Impairment of Fertility Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males. Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown. Usage in Pregnancy Pregnancy Category D (see WARNINGS). Labor and Delivery The effect of Tegretol on human labor and delivery is unknown. Nursing Mothers Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to the newborn during breastfeeding are in the range of 2 to 5 mg daily for Tegretol and 1 to 2 mg daily for the epoxide. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children. Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e. 4 to 12 mcg/mL) is the same in children and adults. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 15 The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available. Geriatric Use No systematic studies in geriatric patients have been conducted. ADVERSE REACTIONS If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED WARNING), the liver, and the cardiovascular system. The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended. The following additional adverse reactions have been reported: Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda. Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis, onychomadesis and hirsutism. In certain cases, discontinuation of therapy may be necessary. Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g. pulmonary embolism), and adenopathy or lymphadenopathy. Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds. Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis, very rare cases of hepatic failure. Pancreatic: Pancreatitis. Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia. Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 16 urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis. Testicular atrophy occurred in rats receiving Tegretol orally from 4 to 52 weeks at dosage levels of 50 to 400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown. Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome. There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs. Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis. Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes. Musculoskeletal System: Aching joints and muscles, and leg cramps. Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium leading to osteoporosis have been reported. Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants. A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine. DRUG ABUSE AND DEPENDENCE No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or physical dependence in humans. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 17 OVERDOSAGE Acute Toxicity Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia). Oral LD50 in animals (mg/kg): mice, 1100 to 3750; rats, 3850 to 4025; rabbits, 1500 to 2680; guinea pigs, 920. Signs and Symptoms The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than 60 g) have been ingested. Respiration: Irregular breathing, respiratory depression. Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders. Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia. Gastrointestinal Tract: Nausea, vomiting. Kidneys and Bladder: Anuria or oliguria, urinary retention. Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias. Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified. Treatment The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote. Elimination of the Drug: Induction of vomiting. Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol. Measures to Reduce Absorption: Activated charcoal, laxatives. Measures to Accelerate Elimination: Forced diuresis. Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 18 Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen. Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered. Convulsions: Diazepam or barbiturates. Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week). Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days. Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery. Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels. A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought. DOSAGE AND ADMINISTRATION (SEE TABLE BELOW) Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medications or diluents. Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. Medication should be taken with meals. Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended to start with low doses (children 6 to 12 years: ½ teaspoon q.i.d.) and to increase slowly to avoid unwanted side effects. Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by administering the same number of mg per day in smaller, more frequent doses (i.e. b.i.d. tablets to t.i.d. suspension). Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-099 NDA 018281/S-047 NDA 018927/S-040 NDA 020234/S-030 FDA Approved Labeling Text dated 9/12/2014 Page 19 Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be noticeable in the stool. Epilepsy (SEE INDICATIONS AND USAGE) Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12 to 15 years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level, usually 800 to 1200 mg daily. Children 6 to 12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or ½ teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level, usually 400 to 800 mg daily. Children under 6 years of age - Initial: 10 to 20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be made. Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug Interactions, and Pregnancy Category D). Trigeminal Neuralgia (SEE INDICATIONS AND USAGE) Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or ½ teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (½ teaspoon) q.i.d. for suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in most patients with 400 to 800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage Information Initial Dose Subsequent Dose Maximum Daily Dose Indication Tablet* XR† Suspension Tablet* XR† Suspension Tablet* XR† Suspension Epilepsy Under 6 yr 10-20 mg/kg/day b.i.d. or t.i.d. 10-20 mg/kg/day q.i.d. Increase weekly to achieve optimal clinical response, t.i.d. or q.i.d. Increase weekly to achieve optimal clinical response, t.i.d. or q.i.d. 35 mg/kg/24 hr (see Dosage and Administration section above) 35 mg/kg/24 hr (see Dosage and Administration section above) 6-12 yr 100 mg b.i.d. (200 mg/day) 100 mg b.i.d. (200 mg/day) ½ tsp q.i.d. (200 mg/day) Add up to 100 mg/day at weekly intervals, t.i.d. or q.i.d. Add 100 mg/day at weekly intervals, b.i.d. Add up to 1 tsp (100 mg)/day at weekly intervals, t.i.d. or q.i.d. 1000 mg/24 hr Over 12 yr 200 mg b.i.d. 200 mg b.i.d. 1 tsp q.i.d. Add up to Add up to Add up to 2 tsp 1000 mg/24 hr (12-15 yr) (400 mg/day) (400 mg/day) (400 mg/day) 200 mg/day at 200 mg/day (200 mg)/day at 1200 mg/24 hr (>15 yr) weekly intervals, t.i.d. or q.i.d. at weekly intervals, b.i.d. weekly intervals, t.i.d. or q.i.d. 1600 mg/24 hr (adults, in rare instances) Trigeminal 100 mg b.i.d. 100 mg b.i.d. ½ tsp q.i.d. Add up to Add up to Add up to 2 tsp 1200 mg/24 hr Neuralgia (200 mg/day) (200 mg/day) (200 mg/day) 200 mg/day in increments of 100 mg every 12 hr 200 mg/day in increments of 100 mg every 12 hr (200 mg)/day in increments of 50 mg (½ tsp) q.i.d. Tablet = Chewable or conventional tablets †XR = Tegretol-XR extended-release tablets Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52 twice on the scored side) Bottles of 100 ............................................................................................................................ NDC 0078-0492-05 Unit Dose (blister pack) Box of 100 (strips of 10) ........................................................................................................... NDC 0078-0492-35 Do not store above 30°C (86°F). Protect from light and moisture. Dispense in tight, light-resistant container (USP). Meets USP Dissolution Test 1. Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the partially scored side) Bottles of 100 ............................................................................................................................ NDC 0078-0509-05 Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP). Meets USP Dissolution Test 2. XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on one side Bottles of 100 ............................................................................................................................ NDC 0078-0510-05 XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on one side Bottles of 100 ............................................................................................................................ NDC 0078-0511-05 XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on one side Bottles of 100 ............................................................................................................................ NDC 0078-0512-05 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) Protect from moisture. Dispense in tight container (USP). Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored Bottles of 450 mL ..................................................................................................................... NDC 0078-0508-83 Shake well before using. Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP). Thorazine® is a registered trademark of GlaxoSmithKline. September 2014 Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE TEGRETOL® and TEGRETOL®-XR (Teg-ret-ol) (carbamazepine) Tablets, Suspension, Chewable Tablets, Extended-Release Tablets Read this Medication Guide before you start taking Tegretol or Tegretol–XR (TEGRETOL) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about TEGRETOL? Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL suddenly can cause serious problems. TEGRETOL can cause serious side effects, including: 1. TEGRETOL may cause rare but serious skin rashes that may lead to death. These serious skin reactions are more likely to happen when you begin taking TEGRETOL within the first four months of treatment but may occur at later times. These reactions can happen in anyone, but are more likely in people of Asian descent. If you are of Asian descent, you may need a genetic blood test before you take TEGRETOL to see if you are at a higher risk for serious skin reactions with this medicine. Symptoms may include: • skin rash • hives • sores in your mouth • blistering or peeling of the skin 2. TEGRETOL may cause rare but serious blood problems. Symptoms may include: • fever, sore throat, or other infections that come and go or do not go away • easy bruising • red or purple spots on your body • bleeding gums or nose bleeds • severe fatigue or weakness 3. Like other antiepileptic drugs, TEGRETOL may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling agitated or restless • panic attacks Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop TEGRETOL without first talking to a healthcare provider. Stopping TEGRETOL suddenly can cause serious problems. You should talk to your healthcare provider before stopping. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. What is TEGRETOL? TEGRETOL is a prescription medicine used to treat: • certain types of seizures (partial, tonic-clonic, mixed) • certain types of nerve pain (trigeminal and glossopharyngeal neuralgia) TEGRETOL is not a regular pain medicine and should not be used for aches or pains. Who should not take TEGRETOL? Do not take TEGRETOL if you: • have a history of bone marrow depression. • are allergic to carbamazepine or any of the ingredients in TEGRETOL. See the end of this Medication Guide for a complete list of ingredients in TEGRETOL. • take nefazodone. • are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. • have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. What should I tell my healthcare provider before taking TEGRETOL? Before you take TEGRETOL, tell your healthcare provider if you: • have or have had suicidal thoughts or actions, depression, or mood problems • have or ever had heart problems • have or ever had blood problems • have or ever had liver problems Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • have or ever had kidney problems • have or ever had allergic reactions to medicines • have or ever had increased pressure in your eye • have any other medical conditions • drink grapefruit juice or eat grapefruit • use birth control. TEGRETOL may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you take birth control and TEGRETOL. • are pregnant or plan to become pregnant. TEGRETOL may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking TEGRETOL. You and your healthcare provider should decide if you should take TEGRETOL while you are pregnant. ▪ If you become pregnant while taking TEGRETOL, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334. • are breastfeeding or plan to breastfeed. TEGRETOL passes into breast milk. You and your healthcare provider should discuss whether you should take TEGRETOL or breastfeed; you should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking TEGRETOL with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take TEGRETOL? • Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy may cause seizures that will not stop (status epilepticus). • Take TEGRETOL exactly as prescribed. Your healthcare provider will tell you how much TEGRETOL to take. • Your healthcare provider may change your dose. Do not change your dose of TEGRETOL without talking to your healthcare provider. • Take TEGRETOL with food. • TEGRETOL-XR Tablets: • Do not crush, chew, or break TEGRETOL-XR tablets. • Tell your healthcare provider if you can not swallow TEGRETOL-XR whole. • TEGRETOL Suspension: • Shake the bottle well each time before use. • Do not take TEGRETOL suspension at the same time you take other liquid medicines. • If you take too much TEGRETOL, call your healthcare provider or local Poison Control Center right away. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What should I avoid while taking TEGRETOL? • Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TEGRETOL until you talk to your healthcare provider. TEGRETOL taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how TEGRETOL affects you. TEGRETOL may slow your thinking and motor skills. What are the possible side effects of TEGRETOL? See “What is the most important information I should know about TEGRETOL?” TEGRETOL may cause other serious side effects. These include: • Irregular heartbeat - symptoms include: o Fast, slow, or pounding heartbeat o Shortness of breath o Feeling lightheaded o Fainting • Liver problems - symptoms include: o yellowing of your skin or the whites of your eyes o dark urine o pain on the right side of your stomach area (abdominal pain) o easy bruising o loss of appetite o nausea or vomiting Get medical help right away if you have any of the symptoms listed above or listed in “What is the most important information I should know about TEGRETOL?” The most common side effects of TEGRETOL include: • dizziness • drowsiness • problems with walking and coordination (unsteadiness) • nausea • vomiting These are not all the possible side effects of TEGRETOL. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. How should I store TEGRETOL? • Do not store TEGRETOL Tablets above 30°C (86°F). • Keep TEGRETOL Tablets dry. • Do not store TEGRETOL Chewable Tablets above 30°C (86°F). • Keep TEGRETOL Chewable Tablets out of the light. • Keep TEGRETOL Chewable Tablets dry. • Store TEGRETOL-XR Tablets at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). • Keep TEGRETOL-XR Tablets dry. • Do not store TEGRETOL Suspension above 30°C (86°F). • Shake well before using. • Keep TEGRETOL Suspension in a tight, light-resistant container. Keep TEGRETOL and all medicines out of the reach of children. General Information about TEGRETOL Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TEGRETOL for a condition for which it was not prescribed. Do not give TEGRETOL to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about TEGRETOL. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for the full prescribing information about TEGRETOL that is written for health professionals. For more information, go to www.pharma.us.novartis.com or call 1-888-669-6682. What are the ingredients in TEGRETOL? Active ingredient: carbamazepine Inactive ingredients: • TEGRETOL Tablets: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200 mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). • TEGRETOL Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. • TEGRETOL-XR Tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200 mg tablets only). This Medication Guide has been approved by the U.S. Food and Drug Administration. Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis Reference ID: 3627171 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:01.364160	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016608s099,018281s047,018927s040,020234s030lbl.pdf', 'application_number': 16608, 'submission_type': 'SUPPL ', 'submission_number': 99}
10,902	N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA Approved labeling dated 01/16/2014 Page 1 Tegretol® carbamazepine USP Chewable Tablets of 100 mg - red-speckled, pink Tablets of 200 mg – pink Suspension of 100 mg/5 mL Tegretol®-XR (carbamazepine extended-release tablets) 100 mg, 200 mg, 400 mg Rx only Prescribing Information WARNINGS SERIOUS DERMATOLOGIC REACTIONS AND HLA-B1502 ALLELE SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS). APLASTIC ANEMIA AND AGRANULOCYTOSIS APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA. ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL, Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 2 DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS. BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS. Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential. DESCRIPTION Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and its structural formula is structural formula Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only). CLINICAL PHARMACOLOGY In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 3 Mechanism of Action Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown. The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been established. Pharmacokinetics In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol. The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age). The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 4 INDICATIONS AND USAGE Epilepsy Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: 1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types. 2. Generalized tonic-clonic seizures (grand mal). 3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General). Trigeminal Neuralgia Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains. CONTRAINDICATIONS Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits. Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated. WARNINGS Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. SJS/TEN and HLA-B1502 Allele Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 5 of the HLA-B gene, HLA-B1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity. Across Asian populations, notable variation exists in the prevalence of HLA-B1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B1502, averaging 2 to 4%, but higher in some groups. HLA-B1502 is present in <1% of the population in Japan and Korea. HLA-B1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans). Prior to initiating Tegretol therapy, testing for HLA-B1502 should be performed in patients with ancestry in populations in which HLA-B1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients positive for HLA-B1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS, Laboratory Tests). Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on Tegretol. The HLA-B1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Tegretol such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B1502 positive patients, when alternative therapies are otherwise equally acceptable. Hypersensitivity Reactions and HLA-A3101 Allele Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA A3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). HLA-A3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (for example, Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese, Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry. The risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to be positive for HLA-A3101. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 6 Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B1502-positive and HLA-A3101-positive patients treated with Tegretol will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B1502-negative and HLA-A3101-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring, have not been studied. Aplastic Anemia and Agranulocytosis Aplastic anemia and agranulocytosis have been reported in association with the use of TEGRETOL (see BOXED WARNING). Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has occurred with Tegretol. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Tegretol should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present, benefits and risks should be carefully considered, and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully monitored. In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may experience hypersensitivity reactions with oxcarbazepine (Trileptal®). Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 7 patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. General Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 8 Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind. The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria. As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased seizure frequency. Usage in Pregnancy Carbamazepine can cause fetal harm when administered to a pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, hypospadias, and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. In treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women. In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung. Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg. Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 9 decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may represent a neonatal withdrawal syndrome. To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. PRECAUTIONS General Before initiating therapy, a detailed history and physical examination should be made. Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE). Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol. AV heart block, including second and third degree block, have been reported following Tegretol treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances. Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug. In addition, rare instances of vanishing bile duct syndrome have been reported. This syndrome consists of a cholestatic process with a variable clinical course ranging from fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts. Some, but not all, cases are associated with features that overlap with other immunoallergenic syndromes such as multiorgan hypersensitivity (DRESS syndrome) and serious dermatologic reactions. As an example there has been a report of vanishing bile duct syndrome associated with Stevens-Johnson syndrome and in another case an association with fever and eosinophilia. Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION). Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 10 Information for Patients Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking Tegretol. Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use. Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the event a skin reaction should occur while taking Tegretol, patients should consult with their physician immediately (see WARNINGS). Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription medications or herbal products. Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive sedative effect. Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks. Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection). Laboratory Tests For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B1502 typing’ is recommended. The test is positive if either one or two HLA-B1502 alleles are detected and negative if no HLA-B1502 alleles are detected. Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 11 newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease. Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes. Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction. Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used. Thyroid function tests have been reported to show decreased values with Tegretol administered alone. Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other drugs. Interference with some pregnancy tests has been reported. Drug Interactions There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION). Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following: Agents That May Affect Tegretol Plasma Levels When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required. Agents That Increase Carbamazepine Levels CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include: Aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, trazodone, loxapine,* olanzapine, quetiapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, protease inhibitors, valproate. Agents That Decrease Carbamazepine Levels CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include: Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 12 cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline. increased levels of the active carbamazepine-10,11-epoxide †decreased levels of carbamazepine and increased levels of the 10,11-epoxide Effect of Tegretol on Plasma Levels of Concomitant Agents Decreased Levels of Concomitant Medications Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of comedications mainly metabolized by CYP3A4 through induction of their metabolism. Tegretol causes, or would be expected to cause, decreased levels of the following: acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertaline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide. In concomitant use with Tegretol, monitoring of concentrations or dosage adjustment of the above agents may be necessary. Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic administration of high doses of another CYP3A4 inducer. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine. When carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination therapy, the aripiprazole dose should be reduced. When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended. The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. Based on pharmacokinetic studies, if patients must be co-administered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered. The use of carbamazepine with lapatinib should generally be avoided. Dosage adjustment should be considered if lapatinib is coadministered with carbamazepine. If carbamazepine is started in a patient already taking Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 13 lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced. Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS). Other Drug Interactions Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity. Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia. Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications. Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered. Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine. Whether or not carbamazepine has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. Carcinogenesis, Mutagenesis, Impairment of Fertility Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males. Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown. Usage in Pregnancy Pregnancy Category D (see WARNINGS). Labor and Delivery The effect of Tegretol on human labor and delivery is unknown. Nursing Mothers Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 14 the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the epoxide. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children. Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults. The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available. Geriatric Use No systematic studies in geriatric patients have been conducted. ADVERSE REACTIONS If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED WARNING), the liver, and the cardiovascular system. The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the low dosage recommended. The following additional adverse reactions have been reported: Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda. Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis and onychomadesis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 15 Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy. Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds. Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure. Pancreatic: Pancreatitis. Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia. Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis. Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown. Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome. There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs. Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis. Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes. Musculoskeletal System: Aching joints and muscles, and leg cramps. Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium leading to osteoporosis have been reported. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 16 Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants. A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine. DRUG ABUSE AND DEPENDENCE No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or physical dependence in humans. OVERDOSAGE Acute Toxicity Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia). Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920. Signs and Symptoms The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (>60 g) have been ingested. Respiration: Irregular breathing, respiratory depression. Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders. Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia. Gastrointestinal Tract: Nausea, vomiting. Kidneys and Bladder: Anuria or oliguria, urinary retention. Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias. Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified. Treatment The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 17 absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote. Elimination of the Drug: Induction of vomiting. Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol. Measures to Reduce Absorption: Activated charcoal, laxatives. Measures to Accelerate Elimination: Forced diuresis. Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children. Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen. Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered. Convulsions: Diazepam or barbiturates. Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week). Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days. Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery. Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels. A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought. DOSAGE AND ADMINISTRATION (SEE TABLE BELOW) Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medications or diluents. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 18 Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. Medication should be taken with meals. Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase slowly to avoid unwanted side effects. Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d. suspension). Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be noticeable in the stool. Epilepsy (SEE INDICATIONS AND USAGE) Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily. Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level, usually 400-800 mg daily. Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be made. Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug Interactions, and Pregnancy Category D). Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 016608/S-103 N 018281/S-051 N 020234/S-035 N 018927/S-044 FDA proposed labeling dated 12/19/2013 Page 19 Trigeminal Neuralgia (SEE INDICATIONS AND USAGE) Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage Information Initial Dose Subsequent Dos e Maximum Dail y Dose Indication Tablet XR † Suspension Tablet* XR † Suspension Tablet* XR † Suspension Epileps y Under 6 yr 10-20 mg/kg/day 10-20 mg/kg/day Increase weekl y Increase 35 mg/kg/24 hr 35 mg/kg/24 hr b.i.d. or t.i.d. q.i.d. to achieve weekly to (see Dosage (see Dosage optimal clinical achieve optimal and and response, t.i.d. clinical Administration Administration or q.i.d. response, t.i.d. section above) section above) or q.i.d. 6-12 yr 100 mg b.i.d. 100 mg b.i.d. ½ tsp q.i.d. Add up to Add Add up to 1 tsp 1000 mg/24 h r (200 mg/day) (200 mg/day) (200 mg/day) 100 mg/day at 100 mg/da y (100 mg)/day at weekly intervals, at weekl y weekl y t.i.d. or q.i.d. intervals, intervals, t.i.d. b.i.d. or q.i.d. Over 12 yr 200 mg b.i.d. 200 mg b.i.d. 1 tsp q.i.d. Add up to Add up to Add up to 2 tsp 1000 mg/24 hr (12-15 yr) (400 mg/day) (400 mg/day) (400 mg/day) 200 mg/day at 200 mg/da y (200 mg)/day at 1200 mg/24 hr (>15 yr) weekly intervals, at weekl y weekl y 1600 mg/24 hr (adults, in rare instances) t.i.d. or q.i.d. intervals, intervals, t.i.d. b.i.d. or q.i.d. Trigeminal 100 mg b.i.d. 100 mg b.i.d. ½ tsp q.i.d. Add up to Add up to Add up to 2 tsp 1200 mg/24 h r Neuralgia (200 mg/day) (200 mg/day) (200 mg/day) 200 mg/day in 200 mg/da y (200 mg)/day increments of in increments in increments 100 mg every of 100 mg of 50 mg 12 hr every 12 hr (½ tsp) q.i.d. Tablet = Chewable or conventional tablets †XR = Tegretol ®-XR extended-release tablets Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52 twice on the scored side) Bottles of 100 ............................................................................................................................ NDC 0078-0492-05 Unit Dose (blister pack) Box of 100 (strips of 10) ........................................................................................................... NDC 0078-0492-35 Do not store above 30°C (86°F). Protect from light and moisture. Dispense in tight, light-resistant container (USP). Meets USP Dissolution Test 1. Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the partially scored side) Bottles of 100 ............................................................................................................................ NDC 0078-0509-05 Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP). Meets USP Dissolution Test 2. XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on one side Bottles of 100 ............................................................................................................................ NDC 0078-0510-05 XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on one side Bottles of 100 ............................................................................................................................ NDC 0078-0511-05 XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on one side Bottles of 100 ............................................................................................................................ NDC 0078-0512-05 Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture. Dispense in tight container (USP). Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored Bottles of 450 mL ..................................................................................................................... NDC 0078-0508-83 Shake well before using. Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP). Thorazine® is a registered trademark of GlaxoSmithKline. T20XX-XX January 2014 Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE TEGRETOL® and TEGRETOL®-XR (Teg-ret-ol) (carbamazepine) Tablets, Suspension, Chewable Tablets, Extended-Release Tablets Read this Medication Guide before you start taking Tegretol or Tegretol –XR (TEGRETOL) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about TEGRETOL? Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL suddenly can cause serious problems. TEGRETOL can cause serious side effects, including: 1. TEGRETOL may cause rare but serious skin rashes that may lead to death. These serious skin reactions are more likely to happen when you begin taking TEGRETOL within the first four months of treatment but may occur at later times. These reactions can happen in anyone, but are more likely in people of Asian descent. If you are of Asian descent, you may need a genetic blood test before you take TEGRETOL to see if you are at a higher risk for serious skin reactions with this medicine. Symptoms may include:  skin rash  hives  sores in your mouth  blistering or peeling of the skin 2. TEGRETOL may cause rare but serious blood problems. Symptoms may include:  fever, sore throat, or other infections that come and go or do not go away  easy bruising  red or purple spots on your body  bleeding gums or nose bleeds  severe fatigue or weakness 3. Like other antiepileptic drugs, TEGRETOL may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:  thoughts about suicide or dying  attempts to commit suicide  new or worse depression  new or worse anxiety Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  feeling agitated or restless  panic attacks  trouble sleeping (insomnia)  new or worse irritability  acting aggressive, being angry, or violent  acting on dangerous impulses  an extreme increase in activity and talking (mania)  other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions?  Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.  Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop TEGRETOL without first talking to a healthcare provider. Stopping TEGRETOL suddenly can cause serious problems. You should talk to your healthcare provider before stopping. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. What is TEGRETOL? TEGRETOL is a prescription medicine used to treat:  certain types of seizures (partial, tonic-clonic, mixed)  certain types of nerve pain (trigeminal and glossopharyngeal neuralgia) TEGRETOL is not a regular pain medicine and should not be used for aches or pains. Who should not take TEGRETOL? Do not take TEGRETOL if you:  have a history of bone marrow depression.  are allergic to carbamazepine or any of the ingredients in TEGRETOL. See the end of this Medication Guide for a complete list of ingredients in TEGRETOL.  take nefazodone.  are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.  have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. What should I tell my healthcare provider before taking TEGRETOL? Before you take TEGRETOL, tell your healthcare provider if you: Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  have or have had suicidal thoughts or actions, depression, or mood problems  have or ever had heart problems  have or ever had blood problems  have or ever had liver problems  have or ever had kidney problems  have or ever had allergic reactions to medicines  have or ever had increased pressure in your eye  have any other medical conditions  drink grapefruit juice or eat grapefruit  use birth control. TEGRETOL may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you take birth control and TEGRETOL.  are pregnant or plan to become pregnant. TEGRETOL may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking TEGRETOL. You and your healthcare provider should decide if you should take TEGRETOL while you are pregnant. ▪ If you become pregnant while taking TEGRETOL, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334.  are breastfeeding or plan to breastfeed. TEGRETOL passes into breast milk. You and your healthcare provider should discuss whether you should take TEGRETOL or breastfeed; you should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking TEGRETOL with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take TEGRETOL?  Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy may cause seizures that will not stop (status epilepticus).  Take TEGRETOL exactly as prescribed. Your healthcare provider will tell you how much TEGRETOL to take.  Your healthcare provider may change your dose. Do not change your dose of TEGRETOL without talking to your healthcare provider.  Take TEGRETOL with food. Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  TEGRETOL-XR Tablets:  Do not crush, chew, or break TEGRETOL-XR tablets.  Tell you healthcare provider if you can not swallow TEGRETOL-XR whole.  TEGRETOL Suspension:  Shake the bottle well each time before use.  Do not take TEGRETOL suspension at the same time you take other liquid medicines.  If you take too much TEGRETOL, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking TEGRETOL?  Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TEGRETOL until you talk to your healthcare provider. TEGRETOL taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.  Do not drive, operate heavy machinery, or do other dangerous activities until you know how TEGRETOL affects you. TEGRETOL may slow your thinking and motor skills. What are the possible side effects of TEGRETOL? See “What is the most important information I should know about TEGRETOL?” TEGRETOL may cause other serious side effects. These include:  Irregular heartbeat - symptoms include: o Fast, slow, or pounding heartbeat o Shortness of breath o Feeling lightheaded o Fainting  Liver problems - symptoms include: o yellowing of your skin or the whites of your eyes o dark urine o pain on the right side of your stomach area (abdominal pain) o easy bruising o loss of appetite o nausea or vomiting Get medical help right away if you have any of the symptoms listed above or listed in “What is the most important information I should know about TEGRETOL”. The most common side effects of TEGRETOL include: Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  dizziness  drowsiness  problems with walking and coordination (unsteadiness)  nausea  vomiting These are not all the possible side effects of TEGRETOL. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. How should I store TEGRETOL?  Do not store TEGRETOL Tablets above 30°C (86°F).  Keep TEGRETOL Tablets dry.  Do not store TEGRETOL Chewable Tablets above 30°C (86°F).  Keep TEGRETOL Chewable Tablets out of the light.  Keep TEGRETOL Chewable Tablets dry.  Store TEGRETOL-XR Tablets between 15°C to 30°C (59°F to 86°F).  Keep TEGRETOL-XR Tablets dry.  Do not store TEGRETOL Suspension above 30°C (86°F).  Shake well before using.  Keep TEGRETOL Suspension in a tight, light-resistant container. Keep TEGRETOL and all medicines out of the reach of children. General Information about TEGRETOL Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TEGRETOL for a condition for which it was not prescribed. Do not give TEGRETOL to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about TEGRETOL. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for the full prescribing information about TEGRETOL that is written for health professionals. For more information, go to www.pharma.us.novartis.com or call 1-888-669-6682. What are the ingredients in TEGRETOL? Active ingredient: carbamazepine Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inactive ingredients:  TEGRETOL Tablets: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only).  TEGRETOL Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.  TEGRETOL-XR Tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only). This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T20XX-XX/T2013-24 January 2014/March 2013 Reference ID: 3437567 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:01.497928	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016608s103,018281s051,018927s044,020234s035lbl.pdf', 'application_number': 16608, 'submission_type': 'SUPPL ', 'submission_number': 103}
10,903	s t r uctur a l f ormu l a Macrodantin® (nitrofurantoin macrocrystals) Capsules To reduce the development of drug-resistant bacteria and maintain the effectiveness of Macrodantin and other antibacterial drugs, Macrodantin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION: Macrodantin is a synthetic chemical of controlled crystal size. It is a stable, yellow, crystalline compound. Macrodantin is an antibacterial agent for specific urinary tract infections. It is available in 25 mg, 50 mg, and 100 mg capsules for oral administration. 1-[[(5-NITRO-2-FURANYL)METHYLENE]AMINO]-2, 4-IMIDAZOLIDINEDIONE Inactive Ingredients: Each capsule contains edible black ink, gelatin, lactose, starch, talc, titanium dioxide, and may contain FD&C Yellow No. 6 and D&C Yellow No. 10. CLINICAL PHARMACOLOGY: Macrodantin is a larger crystal form of Furadantin® (nitrofurantoin). The absorption of Macrodantin is slower and its excretion somewhat less when compared to Furadantin. Blood concentrations at therapeutic dosage are usually low. It is highly soluble in urine, to which it may impart a brown color. Following a dose regimen of 100 mg q.i.d. for 7 days, average urinary drug recoveries (0-24 hours) on day 1 and day 7 were 37.9% and 35.0%. Unlike many drugs, the presence of food or agents delaying gastric emptying can increase the bioavailability of Macrodantin, presumably by allowing better dissolution in gastric juices. MICROBIOLOGY Nitrofurantoin is a nitrofuran antimicrobial agent with activity against certain Gram-positive and Gram-negative bacteria. Mechanism of Action The mechanism of the antimicrobial action of nitrofurantoin is unusual among antibacterials. Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates which inactivate or alter bacterial ribosomal proteins and other acromolecules. As a result of such inactivations, the vital biochemical processes of protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis are inhibited. Nitrofurantoin is bactericidal in urine at therapeutic doses. The broad-based nature of this mode of action may explain the lack of acquired bacterial resistance to nitrofurantoin, as the necessary multiple and simultaneous mutations of the target macromolecules would likely be lethal to the bacteria. Interactions with Other Antibiotics Antagonism has been demonstrated in vitro between nitrofurantoin and quinolone antimicrobials. The clinical significance of this finding is unknown. Development of Resistance Development of resistance to nitrofurantoin has not been a significant problem since its introduction in 1953. Cross-resistance with antibiotics and sulfonamides has not been observed, and transferable resistance is, at most, a very rare phenomenon. Nitrofurantoin has been shown to be active against most strains of the following bacteria both in vitro and in clinical infections [see Indications and Usage): Aerobic and facultative Gram-positive microorganisms: Staphylococcus aureus Enterococci (e.g. Enterococcus faecalis) Aerobic and facultative Gram-negative microorganisms: Escherichia coli NOTE: While nitrofurantoin has excellent activity against Enterococcus faecalis, the majority of Enterococcus faecium isolates are not susceptible to nitrofurantoin. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for nitrofurantoin. However, the efficacy of nitrofurantoin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled trials. Aerobic and facultative Gram-positive microorganisms: Coagulase-negative staphylococci (including Staphylococcus epidermidis and Staphylococcus saprophyticus) Streptococcus agalactiae Group D streptococci Viridans group streptococci Aerobic and facultative Gram-negative microorganisms: Citrobacter amalonaticus Citrobacter diversus Citrobacter freundii Klebsiella oxytoca Reference ID: 3369252 Klebsiella ozaenae NOTE: Some strains of Enterobacter species and Klebsiella species are resistant to nitrofurantoin. Susceptibility Test Methods: When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) (1) or equivalent with standardized inoculum concentrations and standardized concentrations of nitrofurantoin powder. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion technique: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure (2) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 300 Ilg of nitrofurantoin to test the susceptibility of microorganisms to nitrofurantoin. The disk diffusion interpretive criteria are provided in Table 1. Table 1. Susceptibility Interpretive Criteria for Nitrofurantoin Pathogen Susceptibility Interpretive Criteria Minimum Inhibitory Concentrations (µg/mL) Disk Diffusion (zone diameter in mm) S I R S I R Enterobacteriaceae δ32 64 ε128 ε17 15-16 δ14 Staphylococcus spp. δ32 64 ε128 ε17 15-16 δ14 Enterococcus spp. δ32 64 ε128 ε17 15-16 δ14 A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the urine reaches the concentrations usually achievable. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone, which prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the urine reaches the concentrations usually achievable; other therapy should be selected. Quality Control: Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures (3). Standard nitrofurantoin powder should provide the following range of values noted in Table 2. Table 2. Acceptable Quality Control Ranges for Nitrofurantoin QC Strain Acceptable Quality Control Ranges Minimum Inhibitory Concentration (µg/mL) Disk Diffusion (zone diameter in mm) Escherichia coli ATCC 25922 4 – 16 20 -25 Enterococcus faecalis ATCC 29212 4 – 16 NAa Staphylococcus aureus ATCC 29213 8 – 32 NAa Staphylococcus aureus ATCC 25923 NAa 18-22 aNot applicable INDICATIONS AND USAGE: Macrodantin is specifically indicated for the treatment of urinary tract infections when due to susceptible strains of Escherichia coli, enterococci, Staphylococcus aureus, and certain susceptible strains of Klebsiella and Enterobacter species. Nitrofurantoin is not indicated for the treatment of pyelonephritis or perinephric abscesses. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Macrodantin and other antibacterial drugs, Macrodantin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Nitrofurantoins lack the broader tissue distribution of other therapeutic agents approved for urinary tract infections. Consequently, many patients who are treated with Macrodantin are predisposed to persistence or reappearance of bacteriuria. Urine specimens for culture and susceptibility testing should be obtained before and after completion of therapy. If persistence or reappearance of bacteriuria occurs after treatment with Macrodantin, other therapeutic agents with broader tissue distribution should be selected. In considering the use of Macrodantin, lower eradication rates should be balanced against the increased potential for systemic toxicity and for the development of antimicrobial resistance when agents with broader tissue distribution are utilized. CONTRAINDICATIONS: Anuria, oliguria, or significant impairment of renal function (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine) are contraindications. Treatment of this type of patient carries an increased risk of toxicity because of impaired excretion of the drug. Because of the possibility of hemolytic anemia due to immature erythrocyte enzyme systems (glutathione instability), the drug is contraindicated in pregnant patients at term (38-42 weeks’ gestation), during labor and delivery, or when the onset of labor is imminent. For the same reason, the drug is contraindicated in neonates under one month of age. Macrodantin is contraindicated in patients with a previous history of cholestatic jaundice/ hepatic dysfunction associated with nitrofurantoin. Macrodantin is also contraindicated in those patients with known hypersensitivity to nitrofurantoin. WARNINGS: Pulmonary reactions: ACUTE, SUBACUTE, OR CHRONIC PULMONARY REACTIONS HAVE BEEN OBSERVED IN PATIENTS TREATED W ITH NITROFURANTOIN. IF THESE REACTIONS OCCUR, MACRODANTIN SHOULD BE DISCONTINUED AND APPROPRIATE MEASURES TAKEN. REPORTS HAVE CITED PULMONARY REACTIONS AS A CONTRIBUTING CAUSE OF DEATH. CHRONIC PULMONARY REACTIONS (DIFFUSE INTERSTITIAL PNEUMONITIS OR PULMONARY FIBROSIS, OR BOTH) CAN DEVELOP INSIDIOUSLY. THESE REACTIONS OCCUR RARELY AND GENERALLY IN PATIENTS RECEIVING THERAPY FOR SIX MONTHS OR LONGER. CLOSE MONITORING OF THE PULMONARY CONDITION OF PATIENTS RECEIVING LONG-TERM THERAPY IS WARRANTED AND REQUIRES THAT THE BENEFITS OF THERAPY BE WEIGHED AGAINST POTENTIAL RISKS (SEE RESPIRATORY REACTIONS). Hepatotoxicity: Hepatic reactions, including hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis, occur rarely. Fatalities have been reported. The onset of chronic active hepatitis may be insidious, and patients should be monitored periodically for changes in biochemical tests that would indicate liver injury. If hepatitis occurs, the drug should be withdrawn immediately and appropriate measures should be taken. Neuropathy: Peripheral neuropathy, which may become severe or irreversible, has occurred. Fatalities have been reported. Conditions such as renal impairment (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, and debilitating disease may enhance the occurrence of peripheral neuropathy. Patients receiving long-term therapy should be monitored periodically for changes in renal function. Optic neuritis has been reported rarely in postmarketing experience with nitrofurantoin formulations. Hemolytic anemia: Cases of hemolytic anemia of the primaquine-sensitivity type have been induced by nitrofurantoin. Hemolysis appears to be linked to a glucose-6-phosphate dehydrogenase deficiency in the red blood cells of the affected patients. This deficiency is found in 10 percent of Blacks and a small percentage of ethnic groups of Mediterranean and Near-Eastern origin. Hemolysis is an indication for discontinuing Macrodantin; hemolysis ceases when the drug is withdrawn. Clostridium difficile-associated diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including nitrofurantoin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. PRECAUTIONS: Information for Patients: Patients should be advised to take Macrodantin with food to further enhance tolerance and improve drug absorption. Patients should be instructed to complete the full course of therapy; however, they should be advised to contact their physician if any unusual symptoms occur during therapy. Many patients who cannot tolerate microcrystalline nitrofurantoin are able to take Macrodantin without nausea. Patients should be advised not to use antacid preparations containing magnesium trisilicate while taking Macrodantin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should be counseled that antibacterial drugs including Macrodantin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Macrodantin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Macrodantin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. General: Prescribing Macrodantin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Drug Interactions: Antacids containing magnesium trisilicate, when administered concomitantly with nitrofurantoin, reduce both the rate and extent of absorption. The mechanism for this interaction probably is adsorption of nitrofurantoin onto the surface of magnesium trisilicate. Uricosuric drugs, such as probenecid and sulfinpyrazone, can inhibit renal tubular secretion of nitrofurantoin. The resulting increase in nitrofurantoin serum levels may increase toxicity, and the decreased urinary levels could lessen its efficacy as a urinary tract antibacterial. Drug/Laboratory Test Interactions: As a result of the presence of nitrofurantoin, a false- positive reaction for glucose in the urine may occur. This has been observed with Benedict’s and Fehling’s solutions but not with the glucose enzymatic test. Carcinogenesis, Mutagenesis, Impairment of Fertility: Nitrofurantoin was not carcinogenic when fed to female Holtzman rats for 44.5 weeks or to female Sprague-Dawley rats for 75 weeks. Two chronic rodent bioassays utilizing male and female Sprague-Dawley rats and two chronic bioassays in Swiss mice and in BDF1 mice revealed no evidence of carcinogenicity. Nitrofurantoin presented evidence of carcinogenic activity in female B6C3F1 mice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary. In male F344/N rats, there were increased incidences of uncommon kidney tubular cell neoplasms, osteosarcomas of the bone, and neoplasms of the subcutaneous tissue. In one study involving subcutaneous administration of 75 mg/kg nitrofurantoin to pregnant female mice, lung papillary adenomas of unknown significance were observed in the F1 generation. Nitrofurantoin has been shown to induce point mutations in certain strains of Salmonella typhimurium and forward mutations in L5178Y mouse lymphoma cells. Nitrofurantoin induced increased numbers of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells but not in human cells in culture. Results of the sex-linked recessive lethal assay in Drosophila were negative after administration of nitrofurantoin by feeding or by injection. Nitrofurantoin did not induce heritable mutation in the rodent models examined. The significance of the carcinogenicity and mutagenicity findings relative to the therapeutic use of nitrofurantoin in humans is unknown. The administration of high doses of nitrofurantoin to rats causes temporary spermatogenic arrest; this is reversible on discontinuing the drug. Doses of 10 mg/kg/day or greater in healthy human males may, in certain unpredictable instances, produce a slight to moderate spermatogenic arrest with a decrease in sperm count. Pregnancy: Teratogenic effects: Pregnancy Category B. Several reproduction studies have been performed in rabbits and rats at doses up to six times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to nitrofurantoin. In a single published study conducted in mice at 68 times the human dose (based on mg/kg administered to the dam), growth retardation and a low incidence of minor and common malformations were observed. However, at 25 times the human dose, fetal malformations were not observed; the relevance of these findings to humans is uncertain. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic effects: Nitrofurantoin has been shown in one published transplacental carcinogenicity study to induce lung papillary adenomas in the F1 generation mice at doses 19 times the human dose on a mg/kg basis. The relationship of this finding to potential human carcinogenesis is presently unknown. Because of the uncertainty regarding the human implications of these animal data, this drug should be used during pregnancy only if clearly needed. Labor and Delivery: See CONTRAINDICATIONS. Nursing Mothers: Nitrofurantoin has been detected in human breast milk in trace amounts. Reference ID: 3369252 Because of the potential for serious adverse reactions from nitrofurantoin in nursing infants under one month of age, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see CONTRAINDICATIONS). Pediatric Use: Macrodantin is contraindicated in infants below the age of one month (see CONTRAINDICATIONS). Geriatric Use: Clinical studies of Macrodantin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Spontaneous reports suggest a higher proportion of pulmonary reactions, including fatalities, in elderly patients; these differences appear to be related to the higher proportion of elderly patients receiving long-term nitrofurantoin therapy. As in younger patients, chronic pulmonary reactions generally are observed in patients receiving therapy for six months or longer (see WARNINGS). Spontaneous reports also suggest an increased proportion of severe hepatic reactions, including fatalities, in elderly patients (see WARNINGS). In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy should be considered when prescribing Macrodantin. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Anuria, oliguria, or significant impairment of renal function (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine) are contraindications (see CONTRAINDICATIONS). Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS: Respiratory: CHRONIC, SUBACUTE, OR ACUTE PULMONARY HYPERSENSITIVITY REACTIONS MAY OCCUR. CHRONIC PULMONARY REACTIONS OCCUR GENERALLY IN PATIENTS W HO HAVE RECEIVED CONTINUOUS TREATMENT FOR SIX MONTHS OR LONGER. MALAISE, DYSPNEA ON EXERTION, COUGH, AND ALTERED PULMONARY FUNCTION ARE COMMON MANIFESTATIONS WHICH CAN OCCUR INSIDIOUSLY. RADIOLOGIC AND HISTOLOGIC FINDINGS OF DIFFUSE INTERSTITIAL PNEUMONITIS OR FIBROSIS, OR BOTH, ARE ALSO COMMON MANIFESTATIONS OF THE CHRONIC PULMONARY REACTION. FEVER IS RARELY PROMINENT. THE SEVERITY OF CHRONIC PULMONARY REACTIONS AND THEIR DEGREE OF RESOLUTION APPEAR TO BE RELATED TO THE DURATION OF THERAPY AFTER THE FIRST CLINICAL SIGNS APPEAR. PULMONARY FUNCTION MAY BE IMPAIRED PERMANENTLY, EVEN AFTER CESSATION OF THERAPY. THE RISK IS GREATER WHEN CHRONIC PULMONARY REACTIONS ARE NOT RECOGNIZED EARLY. In subacute pulmonary reactions, fever and eosinophilia occur less often than in the acute form. Upon cessation of therapy, recovery may require several months. If the symptoms are not recognized as being drug-related and nitrofurantoin therapy is not stopped, the symptoms may become more severe. Acute pulmonary reactions are commonly manifested by fever, chills, cough, chest pain, dyspnea, pulmonary infiltration with consolidation or pleural effusion on x-ray, and eosinophilia. Acute reactions usually occur within the first week of treatment and are reversible with cessation of therapy. Resolution often is dramatic (see W ARNINGS). Changes in EKG (e.g., non-specific ST/T wave changes, bundle branch block) have been reported in association with pulmonary reactions. Cyanosis has been reported rarely. Hepatic: Hepatic reactions, including hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis, occur rarely (see W ARNINGS). Neurologic: Peripheral neuropathy, which may become severe or irreversible, has occurred. Fatalities have been reported. Conditions such as renal impairment (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, and debilitating diseases may increase the possibility of peripheral neuropathy (see W ARNINGS). Asthenia, vertigo, nystagmus, dizziness, headache, and drowsiness also have been reported with the use of nitrofurantoin. Benign intracranial hypertension (pseudotumor cerebri), confusion, depression, optic neuritis, and psychotic reactions have been reported rarely. Bulging fontanels, as a sign of benign intracranial hypertension in infants, have been reported rarely. Dermatologic: Exfoliative dermatitis and erythema multiforme (including Stevens-Johnson syndrome) have been reported rarely. Transient alopecia also has been reported. Allergic: A lupus-like syndrome associated with pulmonary reactions to nitrofurantoin has been reported. Also, angioedema; maculopapular, erythematous, or eczematous eruptions; pruritus; urticaria; anaphylaxis; arthralgia; myalgia; drug fever; chills; and vasculitis (sometimes associated with pulmonary reactions) have been reported. Hypersensitivity reactions represent the most frequent spontaneously-reported adverse events in worldwide postmarketing experience with nitrofurantoin formulations. Gastrointestinal: Nausea, emesis, and anorexia occur most often. Abdominal pain and diarrhea are less common gastrointestinal reactions. These dose-related reactions can be minimized by reduction of dosage. Sialadenitis and pancreatitis have been reported. There have been sporadic reports of pseudomembranous colitis with the use of nitrofurantoin. The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment (see W ARNINGS). Hematologic: Cyanosis secondary to methemoglobinemia has been reported rarely. Miscellaneous: As with other antimicrobial agents, superinfections caused by resistant organisms, e.g., Pseudomonas species or Candida species, can occur. Laboratory Adverse Events: The following laboratory adverse events have been reported with the use of nitrofurantoin: increased AST (SGOT), increased ALT (SGPT), decreased hemoglobin, increased serum phosphorus, eosinophilia, glucose-6-phosphate dehydrogenase deficiency anemia (see WARNINGS), agranulocytosis, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia, megaloblastic anemia. In most cases, these hematologic abnormalities resolved following cessation of therapy. Aplastic anemia has been reported rarely. OVERDOSAGE: Occasional incidents of acute overdosage of Macrodantin have not resulted in any specific symptoms other than vomiting. Induction of emesis is recommended. There is no specific antidote, but a high fluid intake should be maintained to promote urinary excretion of the drug. It is dialyzable. DOSAGE AND ADMINISTRATION: Macrodantin should be given with food to improve drug absorption and, in some patients, tolerance. Adults: 50-100 mg four times a day -- the lower dosage level is recommended for uncomplicated urinary tract infections. Pediatric Patients: 5-7 mg/kg of body weight per 24 hours, given in four divided doses (contraindicated under one month of age). Therapy should be continued for one week or for at least 3 days after sterility of the urine is obtained. Continued infection indicates the need for reevaluation. For long-term suppressive therapy in adults, a reduction of dosage to 50-100 mg at bedtime may be adequate. For long-term suppressive therapy in pediatric patients, doses as low as 1 mg/kg per 24 hours, given in a single dose or in two divided doses, may be adequate. SEE WARNINGS SECTION REGARDING RISKS ASSOCIATED WITH LONG-TERM THERAPY. HOW SUPPLIED: Macrodantin is available as follows: 25 mg opaque, white capsule imprinted with “MACRODANTIN 25 mg” and “52427-286”. NDC 52427-286-01 bottle of 100 50 mg opaque, yellow and white capsule imprinted with “MACRODANTIN 50 mg” and “52427-287”. NDC 52427-287-01 bottle of 100 100 mg opaque, yellow capsule imprinted with “MACRODANTIN 100 mg” and “52427-288”. NDC 52427-288-01 bottle of 100 Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. REFERENCES 1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Eighth Edition. CLSI document M07-A8 [ISBN 1-56238-689-1]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2009. 2. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-Tenth Edition. CLSI document M02-A 10 [ISBN 1-56238-688-3]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2009. 3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Nineteenth Informational Supplement. CLSI document M100-S19 [ISBN 1-56238-716-2]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2010. Made in USA Distributed by: Almatica Pharma, Inc. Pine Brook, NJ 07058 USA To report SUSPECTED ADVERSE REACTIONS, contact Alvogen, Inc. at 1-866-770-3024 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Rev: 03/2013 PI286-04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:01.572291	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016620s072lbl.pdf', 'application_number': 16620, 'submission_type': 'SUPPL ', 'submission_number': 72}
10,904	NDA 16-624/S-041 Page 3 ALLERGAN HMS (medrysone ophthalmic suspension) 1% Sterile DESCRIPTION HMS (medrysone ophthalmic suspension) 1 % is a topical anti-inflammatory agent for ophthalmic use. Structural Formula: [structure] Medrysone Chemical Name: 11β-hydroxy-6α-methylpregn-4-ene-3,20-dione. Contains: Active: Medrysone 1 %. Preservative: benzalkonium chloride 0.004%. Inactives: edetate disodium; hydroxypropyl methylcellulose; polyvinyl alcohol 1.4%; potassium chloride; purified water; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and sodium hydroxide to adjust the pH (6.2 – 7.5). CLINICAL PHARMACOLOGY HMS (medrysone ophthalmic suspension) is a synthetic corticosteroid with topical anti-inflammatory activity. Corticoidsteroids inhibit the edema, fibrin deposition, capillary dilation, and phagocytic migration of the acute inflammatory response, as well as capillary proliferation, deposition of collagen, and scar formation. HMS (medrysone ophthalmic suspension) has less anti-inflammatory potency than 0.1% dexamethasone. INDICATIONS AND USAGE HMS (medrysone ophthalmic suspension) is indicated for the treatment of allergic conjuctivitis, vernal conjuctivitis, episcleritis, and epinephrine sensitivity. CONTRAINDICATIONS HMS suspension is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. HMS suspension is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids. WARNINGS HMS (medrysone ophthalmic suspension) is not recommended for use in iritis and uveitis as its therapeutic effectiveness has not been demonstrated in these conditions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-624/S-041 Page 4 Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in posterior subcapsular cataract formation. Prolonged use may also suppress the host immune response and thus increase the hazard of secondary ocular infections. Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation. Acute purulent infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication. If this product is used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients. Steroids should be used with caution in the presence of glaucoma. Intraocular pressure should be checked frequently. The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is recommended. Corticosteroids are not effective in mustard gas keratitis and Sjögren’s keratoconjunctivitis. PRECAUTIONS General: The initial prescription and renewal of the medication order beyond 20 milliliters of HMS suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. As fungal infections of the cornea are particularly prone to develop coincidentally with long-term local corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate. If this product is used for 10 days or longer, intraocular pressure should be monitored (see WARNINGS). Information for patients: If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-624/S-041 Page 5 This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children. Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been conducted in animals or in humans to evaluate the potential of these effects. Pregnancy: Teratogenic effects. Pregnancy Category C: Medrysone has been shown to be embryocidal in rabbits when given in doses 10 and 30 times the human ocular dose. Two drops of medrysone were applied to both eyes of pregnant rabbits 4 times per day on day 6 through 18 of gestation. A significant increase in early resorptions was observed in the treated rabbits. There are no adequate and well-controlled studies of medrysone in pregnant women. Medrysone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from medrysone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 3 years have not been established. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients. ADVERSE REACTIONS Adverse reactions include, in decreasing order of frequency, elevation of intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage, posterior subcapsular cataract formation, and delayed wound healing. Although systemic effects are extremely uncommon, there have been rare occurrences of systemic hypercorticoidism after use of topical steroids. Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis and perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids. The development of secondary ocular infection (bacterial, fungal, and viral) has occurred. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-624/S-041 Page 6 Transient burning and stinging upon instillation and other minor symptoms of ocular irritation have been reported with the use of HMS suspension. Other adverse events reported with the use of HMS suspension include: allergic reactions, foreign body sensation, and visual disturbance (blurry vision). OVERDOSAGE Overdosage will not ordinarily cause acute problems. If accidentally ingested, drink fluids to dilute. DOSAGE AND ADMINISTRATION Shake well before using. Instill one drop into the conjunctival sac up to every four hours. HOW SUPPLIED HMS (medrysone ophthalmic suspension) 1% is supplied sterile in opaque white LDPE plastic bottles with droppers with white high impact polystyrene (HIPS) caps as follows: 5 mL in 10 mL bottle - NDC 11980-074-05 10 mL in 15 mL bottle - NDC 11980-074-10 Note: Store at temperatures up to 25ºC (77ºF). Protect from freezing. Rx Only Revised March 2002  2002 Allergan, Inc. Irvine, CA 92612, U.S.A.  Marks owned by Allergan, Inc 6089X This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-624/S-041 Page 7 Containers CONTAINS: Active: Medrysone 1 %. Preservative: benzalkonium chloride 0.004%. Inactives: edetate disodium; hydroxypropyl methylcellulose; polyvinyl alcohol 1.4%; potassium chloride; purified water; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and sodium hydroxide to adjust the pH (6.2 – 7.5). USUAL DOSAGE: Refer to accompanying literature for complete prescribing information. Note: Bottle filled to 1/2 capacity for proper drop control. Protect from freezing. Shake well before using. Allergan, Inc. Irvine, CA 92612, U.S.A.  2002 Allergan, Inc. 6089X Marks owned by Allergan, Inc. ALLERGAN NDC 11980-074-05 5 mL HMS (medrysone ophthalmic suspension) 1% sterile Rx only Cartons 5 mL No. HMS (medrysone ophthalmic suspension) 1% ophthalmic suspension sterile ALLERGAN HMS (medrysone ophthalmic suspension) 1% ophthalmic suspension sterile 5 mL ALLERGAN NDC 11980-074-05 Rx only HMS (medrysone ophthalmic suspension) 1% ophthalmic suspension sterile 5 mL    2002 Allergan, Inc. Irvine, CA 92612, U.S.A. Marks owned by Allergan, Inc. CONTAINS: Active: medrysone 1 %. Preservative: benzalkonium chloride 0.004%. Inactives: edetate disodium; hydroxypropyl methylcellulose; polyvinyl alcohol 1.4%; potassium chloride; purified water; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and sodium hydroxide to adjust the pH (6.2 – 7.5). DOSAGE: Refer to accompanying literature for complete prescribing information. Note: Bottle filled to 1/2 capacity for proper drop control. Protect from freezing. Store in an upright position. Shake well before using. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-624/S-041 Page 8 Containers CONTAINS: Active: Medrysone 1 %. Preservative: benzalkonium chloride 0.004%. Inactives: edetate disodium; hydroxypropyl methylcellulose; polyvinyl alcohol 1.4%; potassium chloride; purified water; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and sodium hydroxide to adjust the pH (6.2 – 7.5). USUAL DOSAGE: Refer to accompanying literature for complete prescribing information. Note: Bottle filled to 1/2 capacity for proper drop control. Protect from freezing. Shake well before using. Allergan, Inc. Irvine, CA 92612, U.S.A.  2002 Allergan, Inc. 6089X Marks owned by Allergan, Inc. ALLERGAN NDC 11980-074-10 10 mL HMS (medrysone ophthalmic suspension) 1% sterile Rx only Cartons 10 mL No. HMS (medrysone ophthalmic suspension) 1% ophthalmic suspension sterile ALLERGAN HMS (medrysone ophthalmic suspension) 1% ophthalmic suspension sterile 10 mL ALLERGAN NDC 11980-074-10 Rx only HMS (medrysone ophthalmic suspension) 1% ophthalmic suspension sterile 10 mL    2002 Allergan, Inc. Irvine, CA 92612, U.S.A. Marks owned by Allergan, Inc. CONTAINS: Active: medrysone 1 %. Preservative: benzalkonium chloride 0.004%. Inactives: edetate disodium; hydroxypropyl methylcellulose; polyvinyl alcohol 1.4%; potassium chloride; purified water; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and sodium hydroxide to adjust the pH (6.2 – 7.5). DOSAGE: Refer to accompanying literature for complete prescribing information. Note: Bottle filled to 1/2 capacity for proper drop control. Protect from freezing. Store in an upright position. Shake well before using. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Wiley Chambers 8/23/02 04:59:07 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:01.684069	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16624s41lbl.pdf', 'application_number': 16624, 'submission_type': 'SUPPL ', 'submission_number': 41}
10,905	Dextrose Injection, USP in AVIVA Plastic Container DESCRIPTION Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, and caloric content are shown in Table 1. Table 1 Size (mL) Dextrose Hydrous, USP (g/L) Osmolarity (mOsmol/L) (calc.) pH nominal (range) Caloric Content (kcal/L) 5% Dextrose Injection, USP 250 500 1000 50 252 4.5 (3.2 to 6.5) 170 10% Dextrose Injection, USP 250 500 1000 100 505 4.5 (3.2 to 6.5) 340 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (see DIRECTIONS FOR USE). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY Dextrose Injection, USP has value as a source of water and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose Injection, USP is indicated as a source of water and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of these solutions can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutive states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of dextrose injections may result in significant hypokalemia. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. PRECAUTIONS General Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Pregnancy Pregnancy Category C There are no adequate and well controlled studies with Dextrose Injection, USP in pregnant women and animal reproduction studies have not been conducted with this drug. Therefore, it is not known whether Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman. Dextrose Injection, USP should be given during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Labor and Delivery Intrapartum maternal intravenous infusion of glucose-containing solutions may produce maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may result in neonatal hypoglycemia following delivery. Consider the potential risks and benefits for each specific patient before administering Dextrose Injection, USP. Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk, caution should be exercised when Dextrose Injection, USP is administered to a nursing woman. Pediatric Use The use of Dextrose Injection, USP in pediatric patients is based on clinical practice (see DOSAGE AND ADMINISTRATION). Newborns – especially those born premature and with low birth weight - are at increased risk of developing hypo- or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Geriatric Use Clinical studies of Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Hypersensitivity reactions, including anaphylaxis and chills. Reactions which may occur because of the injection or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. The dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/ hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose Injection, USP in AVIVA plastic container is available as follows: Code Size (ml) NDC Product Name 6E0062 250 0338-6346-02 5% Dextrose Injection, USP 6E0063 500 0338-6346-03 6E0064 1000 0338-6346-04 6E0162 250 0338-6347-02 10% Dextrose Injection, USP 6E0163 500 0338-6347-03 6E0164 1000 0338-6347-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25° C/ 77° F); brief exposure up to 40° C/ 104° F does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER For Information on Risk of Air Embolism - see PRECAUTIONS To Open Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow “To Add Medication” directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA 07-19-69-267 Rev. December 2014 Baxter and Aviva are trademarks of Baxter International Inc. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dextrose Injection, USP in VIAFLEX Plastic Container DESCRIPTION Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, and caloric content are shown in Table 1. Table 1 Size (mL) Dextrose Hydrous, USP (g/L) Osmolarity (mOsmol/L) (calc.) pH Caloric Content (kcal/L) 5% Dextrose Injection, USP 25 Quad pack 50 Single pack Quad pack Multi pack 100 Single pack Quad pack Multi pack 150 250 500 1000 50 252 4.0 (3.2 to 6.5) 170 10% Dextrose Injection, USP 250 500 1000 100 505 4.0 (3.2 to 6.5) 340 Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological test for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Dextrose Injection, USP has value as a source of water and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose Injection, USP is indicated as a source of water and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of these solutions can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutive states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of dextrose injections may result in significant hypokalemia. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. PRECAUTIONS General Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Pregnancy Pregnancy Category C There are no adequate and well controlled studies with Dextrose Injection, USP in pregnant women and animal reproduction studies have not been conductedwith this drug. Therefore, it is not known whether Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman. Dextrose Injection, USP should be given during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery Intrapartum maternal intravenous infusion of glucose-containing solutions may produce maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may result in neonatal hypoglycemia following delivery. Consider the potential risks and benefits for each specific patient before administering Dextrose Injection , USP. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk, caution should be exercised when a Dextrose Injection, USP is administered to a nursing woman. Pediatric Use The use of Dextrose Injection, USP in pediatric patients is based on clinical practice (see DOSAGE AND ADMINISTRATION). Newborns – especially those born premature and with low birth weight - are at increased risk of developing hypo- or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Geriatric Use Clinical studies of Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Hypersensitivity reactions, including anaphylaxis and chills. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reactions which may occur because of the injection or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. The dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/ hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose Injection, USP in VIAFLEX plastic container is available as follows: Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Code Size (mL) NDC Product Name 25 2B0080 Quad pack 0338- 0017- 10 5% Dextrose Injection, USP 50 2B0086 Single pack 0338-0017-41 5% Dextrose Injection, USP 2B0081 Quad pack 0338-0017-11 2B0088 Multi pack 0338-0017-31 100 2B0087 Single pack 0338-0017-48 5% Dextrose Injection, USP 2B0082 Quad pack 0338-0017-18 2B0089 Multi pack 0338-0017-38 2B0061 150 0338- 0017-01 2B0062 250 0338- 0017-02 2B0063 500 0338- 0017-03 2B0064 1000 0338- 0017-04 2B0162 250 0338- 0023-02 10% Dextrose Injection, USP 2B0163 500 0338- 0023-03 2B0164 1000 0338- 0023-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C/104°F does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER For Information on Risk of Air Embolism - see PRECAUTIONS To Open Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow “To Add Medication” directions below. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA 07-19-69-268 Rev. December 2014 Baxter, PL 146, and Viaflex are trademarks of Baxter International Inc. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 70% Dextrose Injection, USP in VIAFLEX Plastic Container A Parenteral Nutrient DESCRIPTION Dextrose Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid replenishment and caloric supply in single dose container for intravenous administration after compounding. It contains no antimicrobial agents. Composition, osmolarity, pH, and caloric content are shown in Table 1. Table 1 Composition Osmolarity (mOsmol/L) (calc.) pH Caloric Content (kcal/L) How Supplied Dextrose Hydrous, USP (g/L) Size 500 mL in 1000 mL container Code and NDC 70% Dextrose Injection, USP 700 3530 4.0 (3.2 to 6.5) 2390 2B0114 NDC 0338-0719-13 The structural formula of Dextrose Hydrous, USP is: The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). Exposure to temperatures above 25ºC/77ºF during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda changes within the expiration period. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. CLINICAL PHARMACOLOGY Dextrose Injection, USP have value as a source of water and calories. They are capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose Injection, USP are indicated as a caloric component in a parenteral nutrition regimen. They are used with an appropriate protein (nitrogen) source in the prevention of nitrogen loss or in the treatment of negative nitrogen balance in patients where: (1) the alimentary tract cannot or should not be used, (2) gastrointestinal absorption of protein is impaired, or (3) metabolic requirements for protein are substantially increased, as with extensive burns. CONTRAINDICATIONS The infusion of hypertonic dextrose injection is contraindicated in patients having intracranial or intraspinal hemorrhage, in patients who are severely dehydrated, in patients who are anuric, and in patients in hepatic coma. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dilute before use to a concentration which will, when administered with an amino acid (nitrogen) source, result in an appropriate calorie to gram of nitrogen ratio and which has an osmolarity consistent with the route of administration. Unless appropriately diluted, the infusion of hypertonic dextrose injection into a peripheral vein may result in vein irritation, vein damage, and thrombosis. Strongly hypertonic nutrient solutions should only be administered through an indwelling intravenous catheter with the tip located in a large central vein such as the superior vena cava. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. Monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. PRECAUTIONS General Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Administration of hypertonic dextrose and amino acid solutions via central venous catheter may be associated with complications which can be prevented or minimized by careful attention to all aspects of the procedure. This includes attention to solution preparation, administration and patient monitoring. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda It is essential that a carefully prepared protocol, based upon current medical practice, be followed, preferably by an experienced medical team. The package insert of the protein (nitrogen) source should be consulted for dosage and all precautionary information. Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency. Caution must be exercised in the administration of these injections to patients receiving corticosteroids or corticotropin. These injections should be used with caution in patients with overt or subclinical diabetes mellitus. Drug product contains no more than 25 mcg/L of aluminum. Pregnancy Pregnancy Category C There are no adequate and well controlled studies with Dextrose Injections, USP in pregnant women and animal reproduction studies have not been conducted with this drug. Therefore, it is not known whether Dextrose Injections, USP can cause fetal harm when administered to a pregnant woman. Dextrose Injections, USP should be given during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery Intrapartum maternal intravenous infusion of glucose-containing solutions may produce maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may result in neonatal hypoglycemia following delivery. Consider the potential risks and benefits for each specific patient before administering Dextrose Injection, USP. Nursing Mothers It is not known if this drug is present in human milk. Because many drugs are present in human milk, caution should be exercised when Dextrose Injection, USP, is administered to a nursing woman. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use The use of Dextrose is in pediatric patients is based on clinical practice (see DOSAGE AND ADMINISTRATION).Because of their hypertonicity, 70% Dextrose Injection must be diluted prior to administration. Newborns – especially those born premature and with low birth weight - are at increased risk of developing hypo- or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. ADVERSE REACTIONS Too rapid infusion of a hypertonic dextrose solution may result in diuresis, hyperglycemia, glycosuria, and hyperosmolar coma. Continual clinical monitoring of the patient is necessary in order to identify and initiate measures for these clinical conditions. Hypersensitivity reactions, including anaphylaxis and chills. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION Following suitable admixture of prescribed drugs, the dosage is usually dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. See directions accompanying drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. These admixed injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. The dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/ hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgement of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED See Table 1. Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended the product be stored at room temperature (25ºC/77ºF). DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER For Information on Risk of Air Embolism - see PRECAUTIONS Preparation for Administration 1. Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. 2. Insert transfer set into prepared solution container to be transferred. Follow directions accompanying transfer set. 3. Remove protector from extended middle port of dextrose solution container and insert connector of transfer set. 4. Transfer solution by gravity or by using a VIAVAC unit. 5. After desired solution has been transferred, mix thoroughly and seal extension tubing of extended middle port. Cut between seal and connector of transfer set. 6. Check for leaks. 7. Warning: Additives may be incompatible. Supplemental medication may be added with a 19 to 22 gauge needle through the medication injection site on the dextrose solution container. Mix solution and medication thoroughly. For high density medications, such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. 8. Suspend container from eyelet support. 9. Remove plastic protector from outlet port at bottom of container. 10. Attach administration set. Refer to complete directions accompanying set. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA 07-19-65-534 Rev. December 2014 Baxter, PL 146, and Viaflex are trademarks of Baxter International Inc. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 50% and 70% Dextrose Injection, USP Pharmacy Bulk Package Not for Direct Infusion VIAFLEX Plastic Container A Parenteral Nutrient DESCRIPTION Dextrose Injections, USP are sterile, nonpyrogenic hypertonic solutions for fluid replenishment and caloric supply in Pharmacy Bulk Package. A Pharmacy Bulk Package is a container of sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion. They contain no antimicrobial agents. Composition, osmolarity, pH, and caloric content are shown below. Table 1. Composition Osmolarity (mOsmol/L) (calc.) pH Caloric Content (kcal/L) How Supplied Dextrose Hydrous, USP (g/L) Size, code, NDC 2000 mL unit 50% Dextrose Injection, USP 500 2520 4.0 (3.2 to 6.5) 1710 2B0256 NDC 0338-0031-06 70% Dextrose Injection, USP 700 3530 4.0 (3.2 to 6.5) 2390 2B0296 NDC 0338-0719-06 Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as tissue culture toxicity studies. CLINICAL PHARMACOLOGY Dextrose Injection, USP have value as a source of water and calories. They are capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose Injection, USP are indicated as a caloric component in a parenteral nutrition regimen. They are used with an appropriate protein (nitrogen) source in the prevention of nitrogen loss or in the treatment of negative nitrogen balance in patients where: (1) the alimentary tract cannot or should not be used, (2) gastrointestinal absorption of protein is Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda impaired, or (3) metabolic requirements for protein are substantially increased, as with extensive burns. CONTRAINDICATIONS The infusion of hypertonic dextrose injections is contraindicated in patients having intracranial or intraspinal hemorrhage, in patients who are severely dehydrated, in patients who are anuric, and in patients in hepatic coma. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS These injections are for compounding only, not for direct infusion. Dilute before use to a concentration which will, when administered with an amino acid (nitrogen) source, result in an appropriate calorie to gram of nitrogen ratio and which has an osmolarity consistent with the route of administration. Unless appropriately diluted, the infusion of hypertonic dextrose injection into a peripheral vein may result in vein irritation, vein damage, and thrombosis. Strongly hypertonic nutrient solutions should only be administered through an indwelling intravenous catheter with the tip located in a large central vein such as the superior vena cava. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. Administration by central venous catheter should be used only by those familiar with this technique and its complications. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Monitor changes in fluid balance, electrolyte concentration, and acid base balance during prolonged parenteral therapy or whenever the conditions of the patient warrants such evaluation. PRECAUTIONS General Administration of hypertonic dextrose and amino acid solutions via central venous catheter may be associated with complications which can be prevented or minimized by careful attention to all aspects of the procedure. This includes attention to solution preparation, administration and patient monitoring. It is essential that a carefully prepared protocol, based upon current medical practice, be followed, preferably by an experienced medical team. The package insert of the protein (nitrogen) source should be consulted for dosage and all precautionary information. Monitor changes in fluid balance, electrolyte concentration, and acid base balance during prolonged parenteral therapy or whenever the conditions of the patient warrants such evaluation. Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency. Caution must be exercised in the administration of these injections to patients receiving corticosteroids or corticotropin. These injections should be used with caution in patients with overt or subclinical diabetes mellitus. Drug product contains no more than 25 mcg/L of aluminum. Pregnancy Pregnancy Category C There are no adequate and well controlled studies with Dextrose Injections, USP in pregnant women and animal reproduction studies have not been conducted with this drug. Therefore, it is not known whether Dextrose Injections, USP can cause fetal harm when Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administered to a pregnant woman. Dextrose Injections, USP should be given during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery Intrapartum maternal intravenous infusion of glucose-containing solutions may produce maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may result in neonatal hypoglycemia following delivery. Consider the potential risks and benefits for each specific patient before administering Dextrose Injections, USP. Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk, caution should be exercised when 50% and 70% Dextrose Injection, USP is administered to a nursing woman. Pediatric Use The use of Dextrose in pediatric patients is based on clinical practice (see DOSAGE AND ADMINISTRATION). Because of their hypertonicity, 50% and 70% Dextrose Injections must be diluted prior to administration. Newborns – especially those born premature and with low birth weight - are at increased risk of developing hypo- or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. ADVERSE REACTIONS Too rapid infusion of a hypertonic dextrose solution may result in diuresis, hyperglycemia, glycosuria, and hyperosmolar coma. Continual clinical monitoring of the patient is necessary in order to identify and initiate measures for these clinical conditions. Hypersensitivity reactions, including anaphylaxis and chills. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION Following suitable admixture of prescribed drugs, the dosage is usually dependent upon age, weight and clinical condition of the patient as well as laboratory determinations. See directions accompanying drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. Use of a final filter is recommended during administration of all parenteral solutions where possible. The dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/ hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. 50% and 70% Dextrose Injection, USP in the Pharmacy Bulk Package is intended for use in the preparation of sterile, intravenous admixtures. Additives may be incompatible with the fluid withdrawn from this container. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. When compounding admixtures, use aseptic technique. Mix thoroughly. Do not store any unused portion of the 50% and 70% Dextrose Injection, USP. Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIRECTIONS FOR USE OF VIAFLEX PLASTIC PHARMACY BULK PACKAGE CONTAINER To Open Tear overpouch at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. For compounding only, not for direct infusion. Preparation for Admixing 1. The Pharmacy Bulk Package is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). 2. Suspend container from eyelet support. 3. Remove plastic protector from outlet port at bottom of container. 4. Attach solution transfer set. Refer to complete directions accompanying set. Note: The closure shall be penetrated only one time with a suitable sterile transfer device or dispensing set which allows measured dispensing of the contents. 5. The VIAFLEX plastic container should not be written on directly since ink migration has not been investigated. Affix accompanying label for date and time of entry notation. 6. Once container closure has been penetrated, withdrawal of contents should be completed without delay. After initial entry, maintain contents at room temperature (25°C/77°F) and dispense within 4 hours. HOW SUPPLIED See Table 1. Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended the product be stored at room temperature (25°C/77°F). Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Distributed in Canada by Baxter Corporation Mississauga, ON L5N 0C2 Baxter, PL 146, and Viaflex are trademarks of Baxter International Inc. 07-19-69-266 Revised December 2014 Reference ID: 3677008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:01.764450	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/017521s068lbl.pdf', 'application_number': 16673, 'submission_type': 'SUPPL ', 'submission_number': 147}
10,907	07-19-69-742 Baxter Sodium Chloride Injection, USP in AVIVA Plastic Container DESCRIPTION Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The nominal pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below: 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of 1 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. CONTRAINDICATIONS None known. WARNINGS Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Reference ID: 3370968 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Chloride Injection, USP. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also not known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. 3 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. In addition to the above listed adverse reactions, the following has been reported for 0.45% Sodium Chloride Injection, USP (see Pediatric Use section). Reference ID: 3370968 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda - Hyponatremia DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride 6E1314 1000 0338-6333-04 Injection, USP 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride 6E1323 500 0338-6304-03 Injection, USP 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C (104°F) does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be Reference ID: 3370968 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. 6 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only 071969742 07-19-69-742 Revised, September 2013 Baxter and AVIVA are trademarks of Baxter International Inc. For Product Information 1-800-933-0303 Reference ID: 3370968 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-69-741 Baxter Sodium Chloride Injection, USP in VIAFLEX Plastic Container DESCRIPTION Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH is 5.0 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below: 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Reference ID: 3370968 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS None known. WARNINGS Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. The intravenous administration of Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutive states is inversely proportional to the electrolyte concentration of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Reference ID: 3370968 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed with Sodium Chloride Injection, USP to evaluate the potential for carcinogenesis, mutagenesis, or impairment of fertility. Pregnancy: Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also not known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency. 3 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Do not administer unless solution is clear and seal is intact. ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. In addition to the above listed adverse reactions the following has been reported for 0.45% Sodium Chloride Injection, USP (see Pediatric Use section): - Hyponatremia DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. Reference ID: 3370968 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED The available sizes of each injection in VIAFLEX plastic containers are shown below: Code Size (mL) NDC Product Name 2B1313 500 0338-0043-03 0.45% Sodium Chloride Injection, USP 2B1314 1000 0338-0043-04 2B1355 100 0338-1452-48 2B1356 250 0338-1452-02 2B1300 25 Quad Pack 0338-0049-10 0.9% Sodium Chloride Injection, USP 50 2B1306 Single pack 0338-0049-41 2B1301 Quad pack 0338-0049-11 2B1308 Multi pack 0338-0049-31 100 2B1307 Single pack 0338-0049-48 2B1302 Quad pack 0338-0049-18 2B1309 Multi pack 0338-0049-38 2B1321 150 0338-0049-01 2B1322 250 0338-0049-02 2B1323 500 0338-0049-03 2B1324 1000 0338-0049-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C (104°F) does not adversely affect the product. 5 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication WARNING Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. Reference ID: 3370968 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA BAR CODE POSITION ONLY 071969741 07-19-69-741 Rev. September 2013 BAXTER, VIAFLEX and PL 146 are trademarks of Baxter International Inc. 7 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-69-768 Baxter Ringer’s Injection, USP in VIAFLEX Plastic Container DESCRIPTION Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Table 1. Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc) pH Ionic Concentration (mEq/L) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2-2H2 O) Potassium Chloride, USP (KCl) Sodium Potassium Calcium Chloride Ringer’s Injection, USP 500 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 1000 The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 1 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Ringer’s Injection, USP is indicated as a source of water and electrolytes. CONTRAINDICATIONS None known WARNINGS Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. PRECAUTIONS Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. 2 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Pediatric Use The use of Ringer’s Injection, USP in pediatric patients is based on clinical practice. Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Do not administer unless solution is clear and seal is intact. Reference ID: 3370968 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Ringer’s Injection, USP in VIAFLEX plastic container is available as follows: Code Size (mL) NDC 2B2303 500 0338-0105-03 2B2304 1000 0338-0105-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. 4 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication WARNING: Additives may be incompatible To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Reference ID: 3370968 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *BAR CODE POSITION ONLY 071969768 07-19-69-768 Revised September 2013 BAXTER, VIAFLEX AND PL 146 ARE TRADEMARKS OF BAXTER INTERNATIONAL INC. 6 Reference ID: 3370968 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:01.932741	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016677s147,016693s096,018016s061lbl.pdf', 'application_number': 16677, 'submission_type': 'SUPPL ', 'submission_number': 147}
10,909	Sodium Chloride Injection, USP in VIAFLO Plastic Container DESCRIPTION Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The nominal pH is 5.0 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below: 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. VIAFLO is a flexible plastic container fabricated from a multilayer sheeting (PL-2442) composed of Polypropylene (PP), Polyamide (PA) and Polyethylene (PE). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Two different administration connectors are available with VIAFLO containers. The VIAFLO dripless access container (DAC) will not drip once the spike is removed. The non-DAC VIAFLO will drip once the spike is removed from the administration port. CLINICAL PHARMACOLOGY Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. CONTRAINDICATIONS None known. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus have been reported with 0.9% Sodium Chloride Injection, USP. Stop the infusion immediately if signs or symptoms of a hypersensitivity reaction develop, such as tachycardia, chest pain, dyspnea and flushing. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Depending on the volume and rate of infusion, the intravenous administration of Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration/hypervolemia, congested states, pulmonary edema, or acid-base imbalance. The risk of dilutive states is inversely proportional to the electrolyte concentration of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Administer 0.9% Sodium Chloride Injection, USP with particular caution, to patients with or at risk for hypernatremia, hyperchloremia, or metabolic acidosis. Administer Sodium Chloride Injection, USP with particular caution, to patients with or at risk for hypervolemia or with conditions that may cause sodium retention, fluid overload and edema; such as patients with primary hyperaldosteronism, or secondary hyperaldosteronism [e.g., associated with hypertension, congestive heart failure, liver disease (including cirrhosis), renal disease (including renal artery stenosis, nephrosclerosis) or pre-eclampsia]. Certain medications may increase risk of sodium and fluid retention, see Drug Interactions. Administer Sodium Chloride Injection, USP with particular caution, to patients with severe renal impairment. In such patients, administration of Sodium Chloride Injection, USP may result in sodium retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Rapid correction of hypo- and hypernatremia is potentially dangerous (risk of serious neurologic complications). Dosage, rate, and duration of administration should be determined by a physician experienced in intravenous fluid therapy. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised in patients treated with lithium. Renal sodium and lithium clearance may be decreased in the presence of hyponatremia. Renal sodium and lithium clearance may be increased during administration of 0.9% Sodium Chloride Injection, USP. Administration of 0.9% Sodium Chloride Injection, USP, may result in decreased lithium levels. Pregnancy Pregnancy Category C There are no adequate and well controlled studies with Sodium Chloride Injection, USP in pregnant women and animal reproduction studies have not been conducted with this drug. Therefore, it is not known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman. Sodium Chloride Injection, USP should This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be given during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. (See DOSAGE AND ADMINSTRATION). Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been identified during postapproval use of Sodium Chloride Injection, USP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following adverse reactions have been reported in the post-marketing experience during use of 0.9% Sodium Chloride Injection, USP: hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus. Also reported are infusion site reactions, such as infusion site erythema, injection site streaking, burning sensation, and infusion site urticaria. The following adverse reactions have not been reported with 0.9% Sodium Chloride Injection, USP but may occur: hypernatremia, hyperchloremic metabolic acidosis, and hyponatremia, which may be symptomatic. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. OVERDOSAGE Excessive administration of 0.9% Sodium Chloride Injection, USP may lead to hypernatremia. Hypernatremia can lead to CNS manifestations, including seizures, coma, cerebral edema and death. Excessive administration of Sodium Chloride Injection, USP may lead to sodium overload (which can lead to central and/or peripheral edema). When assessing an overdose, any additives in the solution must also be considered. The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION All injections in VIAFLO plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. As directed by a physician. Dosage, rate, and duration of administration are to be individualized and depend upon the indication for use, the patient’s age, weight, clinical condition, concomitant treatment, and on the patient’s clinical and laboratory response to treatment. When other electrolytes or medicines are added to this solution, the dosage and the infusion rate will also be dictated by the dose regimen of the additions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless the solution is clear and seal is intact. Additives may be incompatible with Sodium Chloride Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Sodium Chloride Injection, USP is appropriate. After addition, check for unexpected color changes and/or the appearance of precipitates, insoluble complexes or crystals. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible must not be used. When introducing additives to Sodium Chloride Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. Discard any unused portion. HOW SUPPLIED The available sizes of each 0.9% Sodium Chloride Injection, USP in VIAFLO dripless access containers (DAC) and non-DAC plastic containers are shown below. VIAFLO DAC will not drip once the spike is removed. VIAFLO non-DAC will drip once the spike is removed from the administration port: Code Size (mL) Product NDC UE1322 250 Non-DAC 0338-9543-01 UE1322D 250 DAC 0338-9543-02 UE1323 500 Non-DAC 0338-9543-03 UE1323D 500 DAC 0338-9543-04 UE1324 1000 Non-DAC 0338-9543-05 UE1324D 1000 DAC 0338-9543-06 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C/104°F does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIRECTIONS FOR USE OF VIAFLO PLASTIC CONTAINER For Information on Risk of Air Embolism – see PRECAUTIONS. To Open Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. 1. Remove the container from the over wrap just before use. 2. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. 3. Check solution for clarity and absence of foreign matter. If solution is not clear or contains foreign matter, discard the solution. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. • Grip the small wing on the neck of the port with one hand, • grip the large wing on the cap with the other hand and twist, • the cap will pop off. 3. Use an aseptic method to set up the infusion. 4. Attach administration set. Refer to directions accompanying set for connection, priming of the set and administration of the solution. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, tap ports gently while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by tapping them gently while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Spain SA-30-01-996 Revised XX/2015 Baxter, VIAFLO and PL 2442 are trademarks of Baxter International Inc. Customers can contact Baxter Medical Information at 1-800-933-0303 for more information on the containers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:02.425736	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/016677s150lbl.pdf', 'application_number': 16677, 'submission_type': 'SUPPL ', 'submission_number': 150}
10,908	Sodium Chloride Injection, USP in AVIVA Plastic Container DESCRIPTION Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The nominal pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below: 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) and is hypotonic with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See DIRECTIONS FOR USE). The primary function of the overwrap is to protect the container from the physical environment. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. CONTRAINDICATIONS None known. WARNINGS Hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus have been reported with 0.9% Sodium Chloride Injection, USP and may occur with 0.45% Sodium Chloride Injection, USP. Stop the infusion immediately if signs or symptoms of a hypersensitivity reaction develop, such as tachycardia, chest pain, dyspnea and flushing. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Depending on the volume and rate of infusion, the intravenous administration of Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration/hypervolemia, congested states, pulmonary edema, or acid-base imbalance. The risk of dilutive states is inversely proportional to the electrolyte concentration of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Administer with 0.9% Sodium Chloride Injection, USP with particular caution to patients with or at risk for hypernatremia, hyperchloremia, or metabolic acidosis. The infusion of solutions with 0.45% Sodium Chloride Injection, USP may result in hyponatremia. Close clinical monitoring may be warranted. Hyponatremia can lead to Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda headache, nausea, seizures, lethargy, coma, cerebral edema and death. The risk for hyponatremia is increased, for example, in children, elderly, women, postoperatively, in persons with psychogenic polydipsia, and in patients treated with medications that increase the risk of hyponatremia (such as certain antiepileptic and psychotropic medications). The risk for developing hyponatremic encephalopathy is increased, for example, in pediatric patients (≤16 years of age), women (in particular pre-menopausal women), in patients with hypoxemia, and in patients with underlying central nervous system disease. Acute symptomatic hyponatremic encephalopathy is considered a medical emergency. Administer Sodium Chloride Injection, USP with particular caution to patients with or at risk for hypervolemia or with conditions that may cause sodium retention, fluid overload and edema; such as patients with primary hyperaldosteronism, or secondary hyperaldosteronism [e.g., associated with hypertension, congestive heart failure, liver disease (including cirrhosis), renal disease (including renal artery stenosis, nephrosclerosis) or pre-eclampsia]. Certain medications may increase risk of sodium and fluid retention, see DRUG INTERACTIONS. ADMINISTER Sodium Chloride Injection, USP with particular caution to patients with severe renal impairment. In such patients, administration of Sodium Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Do not mix or administer 0.45% Sodium Chloride Injection, USP through the same administration set with whole blood or cellular blood components. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rapid correction of hypo- and hypernatremia is potentially dangerous (risk of serious neurologic complications). Dosage, rate, and duration of administration should be determined by a physician experienced in intravenous fluid therapy. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised in patients treated with lithium. Renal sodium and lithium clearance may be decreased in the presence of hyponatremia. Administration of 0.45% Sodium Chloride Injection, USP may result in increased lithium levels. Renal sodium and lithium clearance may be increased during administration of 0.9% Sodium Chloride Injection, USP. Administration of 0.9% Sodium Chloride Injection, USP, may result in decreased lithium levels. Pregnancy Pregnancy Category C There are no adequate and well controlled studies with Sodium Chloride Injection, USP in pregnant women and animal reproduction studies have not been conducted with this drug. Therefore, it is not known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman. Sodium Chloride Injection, USP should be given during pregnancy only if only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. (See DOSAGE AND ADMINISTRATION). Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been identified during postapproval use of Sodium Chloride Injection, USP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported in the post-marketing experience during use of 0.9% Sodium Chloride Injection, USP and include the following: hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, pruritus. Also reported are: infusion site reactions, such as infusion site erythema, injection site streaking, burning sensation, and infusion site urticarial. The following adverse reactions have not been reported with 0.9% Sodium Chloride Injection, USP but may occur: hypernatremia, hyperchloremic metabolic acidosis, and hyponatremia, which may be symptomatic. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hyponatremia has been reported for 0.45% Sodium Chloride Injection, USP (see Pediatric Use section). The following adverse reactions have not been reported with 0.45% Sodium Chloride Injection, USP but may occur: hyperchloremic metabolic acidosis, hypersensitivity/infusion reaction (including hypotension, pyrexia, tremor, chills, urticaria, rash and pruritus), and infusion site reactions (such as infusion site erythema, injection site streaking, burning sensation, infusion site urticaria). If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. OVERDOSAGE Excessive administration of 0.45% Sodium Chloride Injection, USP may lead to hypo- and hypernatremia, while excessive administration of 0.9% Sodium Chloride Injection, USP may lead to hypernatremia. Both hypo- and hypernatremia can lead to CNS manifestations, including seizures, coma, cerebral edema and death. Excessive administration of Sodium Chloride Injection, USP may lead to sodium overload (which can lead to central and/or peripheral edema). When assessing an overdose, any additives in the solution must also be considered. The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION All injections in AVIVA plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. As directed by a physician. Dosage, rate, and duration of administration are to be individualized and depend upon the indication for use, the patient’s age, weight, clinical condition, concomitant treatment, and on the patient’s clinical and laboratory response to treatment. When other electrolytes or medicines are added to this solution, the dosage and the infusion rate will also be dictated by the dose regimen of the additions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. Additives may be incompatible with Sodium Chloride Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Sodium Chloride Injection, USP is appropriate. After addition, check for unexpected color changes and/or the appearance of precipitates, insoluble complexes or crystals. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible must not be used. When introducing additives to Sodium Chloride Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. Discard any unused portion. HOW SUPPLIED The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride 6E1314 1000 0338-6333-04 Injection, USP 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride 6E1323 500 0338-6304-03 Injection, USP 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C/104°F does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER For Information on Risk of Air Embolism – see PRECAUTIONS. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Open Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Distributed in Canada by Baxter Corporation Mississauga, ON L5N 0C2 07-19-71-905 Revised, December 2014 Baxter and Aviva are trademarks of Baxter International Inc. For Product Information 1-800-933-0303 Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sodium Chloride Injection, USP in VIAFLEX Plastic Container DESCRIPTION Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The nominal pH is 5.0 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below: 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) and is hypotonic with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The VIAFLEX plastic container is fabricated from a specially formulated polyvinylchloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS None known. WARNINGS Hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus have been reported with 0.9% Sodium Chloride Injection, USP and may occur with 0.45% Sodium Chloride Injection, USP. Stop the infusion immediately if signs or symptoms of a hypersensitivity reaction develop, such as tachycardia, chest pain, dyspnea and flushing. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Depending on the volume and rate of infusion, the intravenous administration of Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration/hypervolemia, congested states, pulmonary edema, or acid-base imbalance. The risk of dilutive states is inversely proportional to the electrolyte concentration of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Administer 0.9% Sodium Chloride Injection, USP with particular caution, to patients with or at risk for hypernatremia, hyperchloremia, or metabolic acidosis. The infusion of solutions with 0.45% Sodium Chloride Injection, USP may result in hyponatremia. Close clinical monitoring may be warranted. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death. The risk for hyponatremia is increased, for example, in children, elderly, women, postoperatively, in persons with psychogenic polydipsia, and in patients treated with medications that increase the risk of hyponatremia (such as certain antiepileptic and psychotropic medications). The risk for developing hyponatremic encephalopathy is increased, for example, in pediatric patients (≤16 years of age), women (in particular pre-menopausal women), in patients with hypoxemia, and in patients with underlying central nervous system disease. Acute symptomatic hyponatremic encephalopathy is considered a medical emergency. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Administer Sodium Chloride Injection, USP with particular caution, to patients with or at risk for hypervolemia or with conditions that may cause sodium retention, fluid overload and edema; such as patients with primary hyperaldosteronism, or secondary hyperaldosteronism [e.g., associated with hypertension, congestive heart failure, liver disease (including cirrhosis), renal disease (including renal artery stenosis, nephrosclerosis) or pre-eclampsia]. Certain medications may increase risk of sodium and fluid retention, see Drug Interactions. Administer Sodium Chloride Injection, USP with particular caution, to patients with severe renal impairment. In such patients, administration of Sodium Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Do not mix or administer 0.45% Sodium Chloride Injection, USP through the same administration set with whole blood or cellular blood components. Rapid correction of hypo- and hypernatremia is potentially dangerous (risk of serious neurologic complications). Dosage, rate, and duration of administration should be determined by a physician experienced in intravenous fluid therapy. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised in patients treated with lithium. Renal sodium and lithium clearance may be decreased in the presence of hyponatremia. Administration of 0.45% Sodium Chloride Injection, USP may result in increased lithium levels. Renal sodium and lithium clearance may be increased during administration of 0.9% Sodium Chloride Injection, USP. Administration of 0.9% Sodium Chloride Injection, USP, may result in decreased lithium levels. Pregnancy Pregnancy Category C There are no adequate and well controlled studies with Sodium Chloride Injection, USP in pregnant women and animal reproduction studies have not been conducted with this drug. Therefore, it is not known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman. Sodium Chloride Injection, USP should be given to a during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. (See DOSAGE AND ADMINSTRATION). Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been identified during postapproval use of Sodium Chloride Injection, USP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported in the post-marketing experience during use of 0.9% Sodium Chloride Injection, USP and include the following: hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus. Also reported are infusion site reactions, such as infusion site erythema, injection site streaking, burning sensation, and infusion site urticaria. The following adverse reactions have not been reported with 0.9% Sodium Chloride Injection, USP but may occur: hypernatremia, hyperchloremic metabolic acidosis, and hyponatremia, which may be symptomatic. Hyponatremia has been reported for 0.45% Sodium Chloride Injection, USP (see Pediatric Use section). Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following adverse reactions have not been reported with 0.45% Sodium Chloride Injection, USP but may occur: hyperchloremic metabolic acidosis, hypersensitivity/infusion reactions (including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus), and infusion site reactions (such as infusion site erythema, injection site streaking, burning sensation, infusion site urticaria). If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. OVERDOSAGE Excessive administration of 0.45% Sodium Chloride Injection, USP may lead to hypo- and hypernatremia, while excessive administration of 0.9% Sodium Chloride Injection, USP may lead to hypernatremia. Both hypo- and hypernatremia can lead to CNS manifestations, including seizures, coma, cerebral edema and death. Excessive administration of Sodium Chloride Injection, USP may lead to sodium overload (which can lead to central and/or peripheral edema). When assessing an overdose, any additives in the solution must also be considered. The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. As directed by a physician. Dosage, rate, and duration of administration are to be individualized and depend upon the indication for use, the patient’s age, weight, clinical condition, concomitant treatment, and on the patient’s clinical and laboratory response to treatment. When other electrolytes or medicines are added to this solution, the dosage and the infusion rate will also be dictated by the dose regimen of the additions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not administer unless the solution is clear and seal is intact. Additives may be incompatible with Sodium Chloride Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Sodium Chloride Injection, USP is appropriate. After addition, check for unexpected color changes and/or the appearance of precipitates, insoluble complexes or crystals. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible must not be used. When introducing additives to Sodium Chloride Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. Discard any unused portion. HOW SUPPLIED The available sizes of each injection in VIAFLEX plastic containers are shown below: Code Size (mL) NDC Product Name 2B1313 500 0338-0043-03 0.45% Sodium Chloride Injection, USP 2B1314 1000 0338-0043-04 2B1356 250 0338-1452-02 2B1300 25 Quad Pack 0338-0049-10 0.9% Sodium Chloride Injection, USP 50 2B1306 Single pack 0338-0049-41 2B1301 Quad pack 0338-0049-11 2B1308 Multi pack 0338-0049-31 100 2B1307 Single pack 0338-0049-48 2B1302 Quad pack 0338-0049-18 2B1309 Multi pack 0338-0049-38 2B1321 150 0338-0049-01 2B1322 250 0338-0049-02 2B1323 500 0338-0049-03 2B1324 1000 0338-0049-04 Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C/104°F does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER For Information on Risk of Air Embolism – see PRECAUTIONS. To Open Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Distributed in Canada by Baxter Corporation Mississauga, ON L5N 0C2 07-19-71-904 Rev. December 2014 Baxter, PL 146, and Viaflex are trademarks of Baxter International Inc. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3% AND 5% SODIUM CHLORIDE INJECTION, USP IN VIAFLEX PLASTIC CONTAINER DESCRIPTION 3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. The pH may have been adjusted with hydrochloric acid. It contains no antimicrobial agents. Composition, ionic concentration, osmolarity, and pH are shown in Table 1. Table 1 Composition (g/L) Ionic Concentration (mEq/L) Osmolarity (mOsmol/L) (calc) pH size (mL) Sodium Chloride USP (NaCl) Sodium Chloride 3% Sodium Chloride Injection, USP 500 30 513 513 1027 5.0 (4.5 to 7.0) 5% Sodium Chloride Injection, USP 500 50 856 856 1711 5.0 (4.5 to 7.0) Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L. The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY 3% and 5% Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE 3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. CONTRAINDICATIONS None known. WARNINGS Hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills, utricaria, rash, and pruritus may occur with 3% and 5% Sodium Chloride Injection, USP. Stop the infusion immediately if signs or symptoms of a hypersensitivity reaction develop, such as tachycardia, chest pain, dyspnea and flushing. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Depending on the volume and rate of infusion, the intravenous administration of 3% and 5% Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration/hypervolemia, congested states, pulmonary edema, or acid-base imbalance. The risk of dilutive states is inversely proportional to the electrolyte concentration of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Administer 3% and 5% Sodium Chloride Injection, USP with particular caution to patients with or at risk for hypernatremia, hypercholermia, hypervolemia or with conditions that may cause sodium retention, fluid overload and edema; such as patients with primary hyperaldosteronism, or secondary hyperaldosteronism (for example, associated with hypertension, congestive heart failure, liver disease (including cirrhosis), renal disease (including renal artery stenosis, nephrosclerosis) or pre-eclampsia). Certain medications may increase risk of sodium and fluid retention, see DRUG INTERACTIONS. Administer 3% and 5% Sodium Chloride Injection, USP with particular caution to patients with severe renal impairment. In such patients administration of Sodium Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. 3% and 5% Sodium Chloride Injection, USP is hypertonic with an osmolarity of 1027 mOsmol/L and 1711 mOsmol/L, respectively. Administration of hypertonic solutions may cause venous damage and thus should be administered through a large vein, for rapid dilution. Do not mix or administer 3% and 5% Sodium Chloride Injection, USP solutions through the same administration set with whole blood or cellular blood components. Rapid correction of hypo- and hypernatremia is potentially dangerous (risk of serious neurologic complications). Dosage, rate, and duration of administration should be determined by a physician experienced in intravenous fluid therapy. Drug Interactions Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised in patients treated with lithium. Renal sodium and lithium clearance may be increased during the administration of 3% and 5% Sodium Chloride Injection, USP. Administration of 3% and 5% Sodium Chloride Injection, USP may, therefore, result in decreased lithium levels. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Pregnancy Category C There are no adequate and well controlled studies with 3% and 5% Sodium Chloride Injection, USP in pregnant women and animal reproduction studies have not been conducted with this drug. Therefore, it is not known whether 3% and 5% Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman. 3% and 5% Sodium Chloride Injection, USP should be given during pregnancy only if the potential benefit justifies the potential risks to the fetus. Nursing Mothers It is not known whether this drug is excreted present in human milk. Because many drugs are excreted present in human milk, caution should be exercised when 3% and 5% Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use The use of 3% and 5% Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. (See DOSAGE AND ADMINISTRATION) Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. Geriatric Use Clinical studies of 3% and 5% Sodium Chloride Injection, USP, did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have not been reported with 3% and 5% Sodium Chloride Injection, USP but may occur: • hyperchloremic metabolic acidosis, • hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus, • Infusion site reactions, such as thrombosis, phlebitis, irritation, infusion site erythema, injection site streaking, burning sensation, infusion site urticaria. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. OVERDOSAGE Excessive administration of 3% and 5% Sodium Chloride Injection, USP may lead to hypernatremia (which can lead to CNS manifestations, including seizures, coma, cerebral edema and death) and sodium overload (which can lead to central and/or peripheral edema). When assessing an overdose, any additives in the solution must also be considered. The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate, and duration of administration are to be individualized and depend upon the indication for use, the patient’s age, weight, clinical condition, concomitant treatment, and on the patient’s clinical and laboratory response to treatment. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. Discard any unused portion. HOW SUPPLIED 3% and 5% Sodium Chloride Injection, USP in VIAFLEX plastic container is available as follows: Code Size (mL) NDC Product Name 2B1353 500 0338-0054-03 3% Sodium Chloride Injection, USP 2B1373 500 0338-0056-03 5% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C /104°F does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER For Information on Risk of Air Embolism – see PRECAUTIONS. To Open Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Warning: Additives may be incompatible - see DOSAGE AND ADMINISTRATION. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA 07-19-72-006 Rev. December 2014 Baxter, PL 146 and Viaflex are trademarks of Baxter International Inc. Reference ID: 3676997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:02.513545	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019022s026lbl.pdf', 'application_number': 16677, 'submission_type': 'SUPPL ', 'submission_number': 148}
10,910	07-19-70-016 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH nominal (range) Ionic Concentration (mEq/L) Caloric Content (kcal/L) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda supplemental medication (See DIRECTIONS FOR USE). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo – or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral oedema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% Sodium Chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. 6 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 500 0338-6315-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1024 1000 0338-6315-04 6E1092 250 0338-6310-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1093 500 0338-6310-03 6E1094 1000 0338-6310-04 6E1082 250 0338-6309-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1083 500 0338-6309-03 6E1084 1000 0338-6309-04 6E1072 250 0338-6308-02 5% Dextrose and 0.45% Sodium Chloride Reference ID: 3370954 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Injection, USP 6E1073 500 0338-6308-03 6E1074 1000 0338-6308-04 6E1062 250 0338-6305-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1063 500 0338-6305-03 6E1064 1000 0338-6305-04 6E1163 500 0338-6314-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1164 1000 0338-6314-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071970016 07-19-70-016 Rev. September 2013 Baxter and AVIVA are trademarks of Baxter International Inc. Reference ID: 3370954 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-70-015 Baxter Dextrose and Sodium Chloride Injection, USP in VIAFLEX Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1. Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH Ionic Concentration (mEq/L) Caloric Content (kcal/L) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo– or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% sodium chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Do not administer unless solution is clear and seal is intact. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Reference ID: 3370954 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in VIAFLEX plastic container is supplied as follows: Code Size (mL) NDC Product Name 2B1023 500 0338-0073-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1024 1000 0338-0073-04 2B1092 250 0338-0077-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 2B1093 500 0338-0077-03 2B1094 1000 0338-0077-04 2B1082 250 0338-0081-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 2B1083 500 0338-0081-03 2B1084 1000 0338-0081-04 2B1072 250 0338-0085-02 5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1073 500 0338-0085-03 2B1074 1000 0338-0085-04 2B1062 250 0338-0089-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1063 500 0338-0089-03 2B1064 1000 0338-0089-04 2B1163 500 0338-0095-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1164 1000 0338-0095-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER 7 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication WARNING Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *For Bar Code Position Only 071970015 07-19-70-15 Rev. September 2013 07-19-70-16 BAXTER, VIAFLEX and PL 146 are trademarks of Baxter International Inc. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:02.529216	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016678s105,016697s096,016689s105,016696s097,016683s100,016687s102lbl.pdf', 'application_number': 16678, 'submission_type': 'SUPPL ', 'submission_number': 105}
10,906	NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 4 Baxter OSMITROL Injection (Mannitol Injection, USP) in AVIVA Plastic Container For Therapeutic Use Only Description Osmitrol Injection (Mannitol Injection, USP) is a sterile, nonpyrogenic solution of Mannitol, USP in a single dose container for intravenous administration. It contains no antimicrobial agents. Mannitol is a six carbon sugar alcohol prepared commercially by the reduction of dextrose. Although virtually inert metabolically in humans, it occurs naturally in fruits and vegetables. Mannitol is an obligatory osmotic diuretic. The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid. Composition, osmolarity, and pH are shown in Table 1. Composition Table 1 Size (mL) Mannitol, USP (g/L) Osmolarity (mOsmol/L) (calc) pH 5% OSMITROL Injection (5% Mannitol Injection, USP) 1000 50 274 5.5 (4.5 TO 7.0) 500 10% OSMITROL Injection (10% Mannitol Injection, USP) 1000 100 549 5.5 (4.5 TO 7.0) 15% OSMITROL Injection (15% Mannitol Injection, USP) 500 150 823 5.5 (4.5 TO 7.0) 250 20% OSMITROL Injection (20% Mannitol Injection, USP) 500 200 1098 5.5 (4.5 TO 7.0) Normal physiologic osmolarity range is approximately 280 to 310 m0smol/L. Administration of substantially hypertonic solutions (≥ 600 m0smol/L) may cause vein damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 5 Mannitol The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for the attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Osmitrol Injection (Mannitol Injection, USP) is one of the nonelectrolyte, obligatory, osmotic diuretics. It is freely filterable at the renal glomerulus, only poorly reabsorbed by the renal tubule, not secreted by the tubule, and is pharmacologically inert. Mannitol, when administered intravenously, exerts its osmotic effect as a solute of relatively small molecular size being largely confined to the extracellular space. Only relatively small amounts of the dose administered is metabolized. Mannitol is readily diffused through the glomerulus of the kidney over a wide range of normal and impaired kidney function. In this fashion, approximately 80% of a 100 gram dose of mannitol will appear in the urine in three hours with lesser amounts thereafter. Even at peak concentrations, mannitol will exhibit less than 10% of tubular reabsorption and is not secreted by tubular cells. Mannitol will hinder tubular reabsorption of water and enhance excretion of sodium This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 6 and chloride by elevating the osmolarity of the glomerular filtrate. This increase in extracellular osmolarity effected by the intravenous administration of mannitol will induce the movement of intracellular water to the extracellular and vascular spaces. This action underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and elevated intraocular pressure. Indications and Usage Osmitrol Injection (Mannitol Injection, USP) is indicated for: The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established; The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass; The reduction of elevated intraocular pressure when the pressure cannot be lowered by other means, and promoting the urinary excretion of toxic substances. Contraindications Osmitrol Injection (Mannitol Injection, USP) is contraindicated in patients with: Well established anuria due to severe renal disease, severe pulmonary congestion or frank pulmonary edema, active intracranial bleeding except during craniotomy, severe dehydration,Progressive renal damage or dysfunction after institution of mannitol therapy, including increasing oliguria and azotemia, and progressive heart failure or pulmonary congestion after institution of mannitol therapy. Warnings In patients with severe impairment of renal function, a test dose should be utilized (see Dosage and Administration). A second test dose may be tried if there is an inadequate response, but no more than two test doses should be attempted. The obligatory diuretic response following rapid infusion of 15% or 20% mannitol injection may further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol administration. If urine output continues to decline during mannitol infusion, the patient’s clinical status should be closely reviewed and mannitol infusion suspended if necessary. Accumulation of mannitol may result in overexpansion of the extracellular fluid which may intensify existing or latent congestive heart failure. Excessive loss of water and electrolytes may lead to serious imbalances. With continued administration of mannitol, loss of water in excess of electrolytes can cause hypernatremia. Electrolyte measurements, including sodium and potassium, are therefore, of vital importance in monitoring the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 7 infusion of mannitol. Osmotic nephrosis, a reversible vacuolization of the tubules of unknown clinical significance, may proceed to severe irreversible nephrosis, so that the renal function must be closely monitored during mannitol infusion. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. The cardiovascular status of the patient should be carefully evaluated before rapidly administrating mannitol since sudden expansion of the extracellular fluid may lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following mannitol infusion may lower serum sodium concentration and aggravate preexisting hyponatremia. By sustaining diuresis, mannitol administration may obscure and intensify inadequate hydration or hypovolemia. Electrolyte free mannitol should not be given conjointly with blood. If it is essential that blood be given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination. When exposed to low temperatures, solutions of mannitol may crystallize. Concentrations greater than 15% have a greater tendency to crystallization. Inspect for crystals prior to administration. If crystals are visible, redissolve by warming the solution up to 70°C, with agitation. Allow the solution to cool to room temperature before reinspection for crystals. Administer intravenously using sterile, filter- type administration set. Laboratory Tests Although blood levels of mannitol can be measured, there is little if any clinical virtue in doing so. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 8 The appropriate monitoring of blood levels of sodium and potassium; degree of hemoconcentration or hemodilution, if any; indices of renal, cardiac and pulmonary function are paramount in avoiding excessive fluid and electrolyte shifts. The routine features of physical examination and clinical chemistries suffice in achieving an adequate degree of appropriate patient monitoring. Drug Interaction Studies have not been conducted to evaluate drug/drug or drug/food interactions with Osmitrol Injection (Mannitol Injection, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with Osmitrol Injection (Mannitol Injection, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with mannitol. It is also not known whether mannitol can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Mannitol should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Osmitrol Injection (Mannitol Injection, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mannitol is administered to a nursing woman. Pediatric Use Safety and effectiveness in children below the age of 12 have not been established. Usage in Children Dosage requirements for patients 12 years of age and under have not been established. Geriatric Use Clinical studies of Osmitrol Injection (Mannitol Injection, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 9 to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Extensive use of mannitol over the last several decades has produced recorded adverse events, in a variety of clinical settings, that are isolated or idiosyncratic in nature. None of these adverse reactions have occurred with any great frequency nor with any security in attributing them to mannitol. The inability to clearly exclude the drug related nature of such events in these isolated reports prompts the necessity to list the reactions that have been observed in patients during or following mannitol infusion. In this fashion, patients have exhibited nausea, vomiting, rhinitis, local pain, skin necrosis and thrombophlebitis at the site of infection, chills, dizziness, urticaria, hypotension, hypertension, tachycardia, fever and angina-like chest pains. Of far greater clinical significance is a variety of events that are related to inappropriate recognition and monitoring of fluid shifts. These are not intrinsic adverse reactions to the drug but the consequence of manipulating osmolarity by any agency in a therapeutically inappropriate manner. Failure to recognize severe impairment of renal function with the high likelihood of nondiuretic response can lead to aggravated dehydration of tissues and increased vascular fluid load. Induced diuresis in the presence of preexisting hemoconcentration and preexisting deficiency of water and electrolytes can lead to serious imbalances. Expansion of the extracellular space can aggravate cardiac decompensation or induce it in the presence of latent heart failure. Pulmonary congestion or edema can be seriously aggravated with the expansion of the extracellular and therefore intravascular fluid load. Hemodilution and dilution of the extracellular fluid space by osmotic shift of water can induce or aggravate preexisting hyponatremia. If unrecognized, such fluid and/or electrolyte shift can produce the reported adverse reactions of pulmonary congestion, acidosis, electrolyte loss, dryness of mouth, thirst, edema, headache, blurred vision, convulsions and congestive cardiac failure. These are not truly adverse reactions to the drug and can be appropriately prevented by evaluation of degree of renal failure with a test dose response to mannitol when indicated; evaluation of hypervolemia and hypovolemia; sodium and potassium levels; hemodilution or hemoconcentration; and evaluation of renal, cardiac and pulmonary function at the onset of therapy. Dosage and Administration Osmitrol Injection (Mannitol Injection, USP) should be administered only by intravenous infusion. The total dosage, concentration, and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement, and urinary output. The usual adult dosage ranges from 20 to 100 g in a 24 hour period, but in most instances an adequate response will be achieved at a dosage of approximately 50 to 100 g in a 24 hour period. The rate of administration is usually adjusted to maintain a urine flow of at least 30 to 50 mL/hour. This outline of administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 10 and dosage is only a general guide to therapy. Parenteral dug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. Test Dose: A test dose of mannitol should be given prior to instituting Osmitrol Injection (Mannitol Injection, USP) therapy for patients with marked oliguria, or those believed to have inadequate renal function. Such a test dose may be approximately 0.2 g/kg body weight (about 75 mL of a 20% solution or 100 mL of a 15% solution) infused in a period of three to five minutes to produce a urine flow of at least 30 to 50 mL/hour. If urine flow does not increase, a second test dose may be given; if there is an inadequate response, the patient should be reevaluated. Prevention of Acute Renal Failure (Oliguria): When used during cardiovascular and other types of surgery, 50 to 100 g of mannitol as a 5, 10, or 15% solution may be given. The concentration will depend upon the fluid requirements of the patient. Treatment of Oliguria: The usual dose for treatment of oliguria is 100 g administered as a 15 or 20% solution. Reduction of Intraocular Pressure: A dose of 1.5 to 2.0 g/kg as a 20% solution (7.5 to 10 mL/kg) or as a 15% solution (10 to 13 mL/kg) may be given over a period as short as 30 minutes in order to obtain a prompt and maximal effect. When used preoperatively the dose should be given one to one and one- half hours before surgery to achieve maximal reduction of intraocular pressure before operation. Reduction of Intracranial Pressure: Usually a maximum reduction in intracranial pressure in adults can be achieved with a dose of 0.25 g/kg given not more frequently than every six to eight hours. An osmotic gradient between the blood and cerebrospinal fluid of approximately 10 m0smols will yield a satisfactory reduction in intracranial pressure. Adjunctive Therapy for Intoxications: As an agent to promote diuresis in intoxications, 5%, 10%, 15% or 20% mannitol is indicated. The concentration will depend upon the fluid requirement and urinary output of the patient. Measurement of glomerular filtration rate by creatinine clearance may be useful for determination of dosage. All injections in AVIVA containers are intended for intravenous administration using sterile equipment. The use of supplemental additive medication is not recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 11 How Supplied Osmitrol Injection (Mannitol Injection, USP) in AVIVA plastic containers is available as follows: Code Size (mL) NDC Product Name 6E5604 1000 0338-6300-04 5% Osmitrol Injection (5% Mannitol Injection, USP) 6E5613 6E5614 500 1000 0338-6301-03 0338-6301-04 10% Osmitrol Injection (10% Mannitol Injection, USP) 6E5623 500 0338-6302-03 15% Osmitrol Injection (15% Mannitol Injection, USP) 6E5632 6E5633 250 500 0338-6303-02 0338-6303-03 20% Osmitrol Injection (20% Osmitrol Injection) Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 12 ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, OSMITROL, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 13 Baxter Sodium Chloride Injection, USP in AVIVA Plastic Container Description Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below. 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 14 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Contraindications None known. Warnings Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 15 Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 16 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride Injection, USP 6E1314 1000 0338-6333-04 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride Injection, USP 6E1323 500 0338-6304-03 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C(104°F) does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 17 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. For Product Information 1-800-833-0303 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 18 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 19 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 20 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 21 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 22 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 23 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 24 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 25 Baxter Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 600 mg Sodium Chloride, USP (NaCl); 310 mg Sodium Lactate (C3H5NaO3); 30 mg of Potassium Chloride, USP (KCl); and 20 mg Calcium Chloride, USP (CaCl2•2H20). It contains no antimicrobial agents. Approximate pH 5.0 (4.0 to 6.5). c * D-Glucopyranose monohydrate Lactated Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 130 mEq sodium, 4 mEq potassium, 2.7 mEq calcium, 109 mEq chloride and 28 mEq lactate. The osmolarity is 525 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 26 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Lactated Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s and 5% Dextrose Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Lactated Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care. If at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting is dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 27 electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Lactated Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Lactated Ringer’s and 5% Dextrose Injection, USP is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Lactated Ringer's and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Lactated Ringer's and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 28 Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer's and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of lactated ringer’s and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum amorality and possible hemorrhage. Geriatric Use Clinical studies of Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Allergic reactions or anaphylactic symptoms such as localized or generalized urinary and purities; per orbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 29 reported during administration of Lactated Ringer’s and 5% Dextrose Injection, USP. The reporting frequency of these signs and symptoms is higher in women during pregnancy. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasations, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size NDC 6E2073 500 mL NDC 0338-6306-03 6E2074 1000 mL NDC 0338-6306-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 30 To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 31 All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 32 Baxter Lactated Ringer’s Injection, USP in AVIVA Plastic Container Description Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP, (NaCl) Sodium Lactate, (C3H5NaO3) Potassium Chloride, USP, (KCl) Calcium Chloride, USP (CaCl2·2H2O) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride Lactate Caloric Content (kcal/L) 250 500 Lactated Ringer’s Injection, USP 1000 6 3.1 0.3 0.2 273 6.5 (6.0 to 7.5) 130 4 2.7 109 28 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 33 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Lactated Ringer’s Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Lactated Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. In patients with diminished renal function, administration of Lactated Ringer’s Injection, USP may result in sodium or potassium retention. Lactated Ringer’s injection, USP is not for use in the treatment of lactic acidosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 34 Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s Injections, USP must be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Test CLINICAL EVALUATION AND PERIODIC LABORATORY DETERMINATIONS ARE NECESSARY TO MONITOR CHANGES IN FLUID BALANCE, ELECTROLYTE CONCENTRATIONS, AND ACID BASE BALANCE DURING PROLONGED PARENTERAL THERAPY OR WHENEVER THE CONDITION OF THE PATIENT WARRANTS SUCH EVALUATION. Drug Interactions Caution must be exercised in the administration of Lactated Ringer's Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Lactated Ringer's Injection, USP. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY STUDIES WITH LACTATED RINGER'S INJECTION, USP HAVE NOT BEEN PERFORMED TO EVALUATE CARCINOGENIC POTENTIAL, MUTAGENIC POTENTIAL, OR EFFECTS ON FERTILITY. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer's Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 35 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer's Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Allergic reactions or anaphylactoid symptoms such as localized or generalized urticaria and pruritis; periorbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been reported during administration of Lactated Ringer’s Injection, USP. The reporting frequency of these signs and symptoms is higher in women during pregnancy. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of infection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 36 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Lactated Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2322 250 0338-6307-02 6E2323 500 0338-6307-03 6E2324 1000 0338-6307-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40° C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 37 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 38 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 39 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 40 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 41 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 42 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 43 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 44 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 45 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 46 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 47 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 48 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 49 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 50 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 51 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 52 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 53 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 54 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 55 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 56 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 57 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 58 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 59 Baxter Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA Plastic Container Description Sodium Lactate Injection, USP (M/6 Sodium Lactate) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with lactic acid. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Lactate (C3H5NaO3) Osmolarity (mOsmol/L) (calc) pH Sodium Lactate Caloric Content (kcal/L) 500 Sodium Lactate Injection, USP (M/6 Sodium Lactate) 1000 18.7 334 6.5 (6.0 to 7.3) 167 167 54 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 60 (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Lactate Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Sodium Lactate Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Sodium Lactate Injection, USP is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications None known Warnings Sodium Lactate Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Sodium Lactate Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of these injections can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Excessive administration of Sodium Lactate Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Sodium Lactate Injection, USP may result in sodium retention. Sodium Lactate Injection, USP is not for use in the treatment of lactic acidosis. Precautions General This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 61 Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Lactate Injection, USP (M/6 Sodium Lactate) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Lactate Injection, USP (M/6 Sodium Lactate). Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Lactate Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Lactate Injection, USP. It is also not known whether Sodium Lactate Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Lactate Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Lactate Injection, USP (M/6 Sodium Lactate) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Lactate Injection, USP is administered to a nursing mother. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 62 Pediatric Use Safety and effectiveness of Sodium Lactate Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium lactate solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Lactate Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 63 How Supplied Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E1803 500 0338-6311-03 6E1804 1000 0338-6311-04 EXPOSURE OF PHARMACEUTICAL PRODUCTS TO HEAT SHOULD BE MINIMIZED. AVOID EXCESSIVE HEAT. IT IS RECOMMENDED THE PRODUCT BE STORED AT ROOM TEMPERATURE (25°C); BRIEF EXPOSURE UP TO 40°C DOES NOT ADVERSELY AFFECT THE PRODUCT. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 64 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 65 Baxter Ringer’s Injection, USP in AVIVA Plastic Container Description Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2·2H2O) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride 500 Ringer’s Injection, USP 1000 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 66 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 67 edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer’s Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 68 Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 69 All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2303 500 NDC 0338-6312-03 6E2304 1000 NDC 0338-6312-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 70 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 71 Baxter Ringer’s Injection, USP in AVIVA Plastic Container Description Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2·2H2O) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride 500 Ringer’s Injection, USP 1000 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 72 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 73 Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer’s Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 74 Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2303 500 NDC 0338-6312-03 6E2304 1000 NDC 0338-6312-04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 75 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 76 Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 77 Baxter Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Ringer’s and 5% Dextrose Injection, USP is sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 860 mg of Sodium Chloride, USP (NaCl); 33 mg of Calcium Chloride, USP (CaCl2•2H2O); and 30 mg of Potassium Chloride, USP (KCl). It contains no antimicrobial agents. The pH is 4.0 (3.5 to 6.5). c D-Glucopyranose monohydrate Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 147.5 mEq sodium, 4.5 mEq calcium, 4 mEq potassium, and 156 mEq chloride. The osmolarity is 561 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 170 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 78 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 79 Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer's and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer's and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer's and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer's and 5% Dextrose Injection, USP. It is also not known whether Ringer's and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer's and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer's and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer's and 5% Dextrose Injection, USP is administered to a nursing woman. Pediatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 80 Safety and effectiveness of Ringer's and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of ringer's and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Ringer's and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 81 of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer's and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2064 1000 NDC 0338-6313-04 6E2063 500 NDC 0338-6313-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C): brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 82 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter Healthcare International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 83 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 84 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 85 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 86 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 87 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 88 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 89 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 90 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 91 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 92 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 93 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 94 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 95 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 96 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 97 Baxter PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 98 Clinical Pharmacology PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE 148 Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. Contraindications None known Warnings PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 99 In patients with diminished renal function, administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA- LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 100 Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 101 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2534 1000 NDC 0338-6316-04 6E2533 500 NDC 0338-6316-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 102 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 103 Baxter PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0). PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a sousrce of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 lcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 104 Clinical Pharmacology PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE A Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. Contraindications None known Warnings PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 105 overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 106 A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elkerly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 107 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2544 1000 NDC 0338-6317-04 6E2543 500 NDC 0338-6317-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 108 To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 109 Baxter PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 234 mg Sodium Chloride, USP (NaCl); 128 mg Potassium Acetate, USP (C2H3KO2); and 32 mg Magnesium Acetate, Tetrahydrate (C4H6MgO4•4H2O). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The osmolarity is 363 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 170 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 110 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 111 PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 112 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 113 selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 114 6E2573 500 NDC 0338-6318-03 6E2574 1000 NDC 0338-6318-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 115 Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 116 Baxter PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in AVIVA Plastic Container Description PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 161 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 138 mg Sodium Lactate (C3H5NaO3), 119 mg Potassium Chloride, USP (KCl), 94 mg Sodium Chloride, USP (NaCl), 37 mg Calcium Chloride, USP (CaCl2•2H2O), and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 16 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 40 mEq chloride, 12 mEq acetate, and 12 mEq lactate. The osmolarity is 377 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 117 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 118 administration of lactate or acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) containing sodium or potassium ions may result in sodium or potassium retention. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 119 Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). It is also not known whether PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 120 In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 121 of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in AVIVA plastic containers is available as shown below: Size (mL) Code NDC 1000 6E2564 NDC 0338-6319-04 500 6E2563 NDC 0338-6319-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 122 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 123 Baxter PLASMA-LYTE R INJECTION (Multiple Electrolytes Injection, Type 2, USP) in AVIVA Plastic Container Description PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 640 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 496 mg of Sodium Chloride, USP (NaCl); 89.6 mg of Sodium Lactate (C3H5NaO3); 74.6 mg of Potassium Chloride, USP (KCl); 36.8 mg of Calcium Chloride, USP (CaCl2•2H2O); and 30.5 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 10 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 103 mEq chloride, 47 mEq acetate, and 8 mEq lactate. The osmolarity is 312 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 11 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 124 PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate or acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) may result in sodium or potassium retention. PLASMA-LYTE R This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 125 Injection (Multiple Electrolytes Injection, Type 2, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP). It is also not known whether PLASMA- LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 126 Studies have not been conducted to evaluate the effects of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 127 Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2504 1000 NDC 0338-6320-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 128 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 129 Baxter PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 526 mg Sodium Chloride, USP (NaCl); 502 mg Sodium Gluconate (C6H11NaO7); 368 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O), 37 mg Potassium Chloride, USP (KCl); and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate and 23 mEq gluconate. The osmolarity is 547 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (>600 mOsmol/L) may cause vein damage. The caloric content is 190 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 130 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories, or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 131 The intravenous administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 132 Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 133 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Size (mL) Code NDC 1000 6E2584 NDC 0338-6321-04 500 6E2583 NDC 0338-6321-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 134 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 135 XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 136 Baxter 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 260 mg Sodium Lactate (C3H5NaO3), 141 mg Potassium Chloride, USP (KCl), 31 mg Magnesium Chloride, USP (MgCl2•6H20), 20 mg Monobasic Potassium Phosphate, NF (KH2PO4), and 12 mg Sodium Chloride, USP (NaCl). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). c D-Glucopyranose monohydrate 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 25 mEq sodium, 20 mEq potassium, 3 mEq magnesium, 24 mEq chloride, 23 mEq lactate and 3 mEq phosphate as HPO4 =. The osmolarity is 348 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 137 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 138 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Do not administer simultaneously with blood. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 139 Drug Interactions Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and electrolytes solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemmorhage. Geriatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 140 Clinical studies of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 141 How Supplied 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2102 250 NDC 0338-6322-02 6E2103 500 NDC 0338-6322-03 6E2104 1000 NDC 0338-6322-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 142 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 143 Baxter Potassium Chloride in 5% Dextrose Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. HO O OH • H O OH OH HO 2 * D-Glucose monohydrate Composition (g/L) Ionic Concentration (mEq/L) Table 1 Potassium Chloride in 5% Dextrose Injection, USP mEq Potassium Size (mL) *Dextrose Hydrous, USP Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Potassium Chloride Caloric Content (kcal/L) 10 mEq 1000 50 0.75 272 4.5 (3.5 to 6.5) 10 10 170 20 mEq 1000 50 1.5 293 4.5 (3.5 to 6.5) 20 20 170 30 mEq 1000 50 2.24 312 4.5 (3.5 to 6.5) 30 30 170 40 mEq 1000 20 mEq 500 50 3 333 4.5 (3.5 to 6.5) 40 40 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 144 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwarp is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose Injection, USP is a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Potassium Chloride in 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The bag label for these injections bears the statement: Do not administer simultaneously with blood. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 145 The intravenous administration of Potassium Chloride in 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose Injection, USP may result in potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Potassium Chloride in 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Studies have not been conducted to evaluate drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose Injection, USP. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 146 Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see Indication and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 147 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Potassium Chloride in 5% Dextrose Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1124 1000 0338-6323-04 10 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1134 1000 0338-6324-04 20 mEq Potassium Chloride in 5% Dextrose Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 148 6E1174 1000 0338-6325-04 30 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1264 1000 0338-6326-04 40 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1263 500 0338-6326-03 20 mEq Potassium Chloride in 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 149 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 150 Baxter Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in Sodium Chloride Injection, USP is a sterile, nonpyrogenic, solution for fluid and electrolyte replenishment in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (Calc.) pH Sodium Potassium Chloride 20 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 1000 9 1.5 348 5.5 (3.5 to 6.5) 154 20 174 40 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 1000 9 3 388 5.5 (3.5 to 6.5) 154 40 194 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 151 (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. The intravenous administration of Potassium Chloride in Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in Sodium Chloride Injection, USP may result in sodium or potassium retention. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 152 Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 153 Safety and effectiveness of Potassium Chloride in Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Geriatric Use Clinical studies of Potassium Chloride in Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 154 Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows: Code Size (mL) NDC Product Name 6E1764 1000 0338-6327-04 20 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 6E1984 1000 0338-6328-04 40 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25º C/77° F); brief exposure up to 40º C (104º F) does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 155 To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 156 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 157 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 158 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 159 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 160 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 161 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 162 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 163 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 164 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 165 Baxter Sodium Chloride Injection, USP in AVIVA Plastic Container Description Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below. 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 166 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Contraindications None known. Warnings Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 167 Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 168 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride Injection, USP 6E1314 1000 0338-6333-04 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride Injection, USP 6E1323 500 0338-6304-03 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C(104°F) does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 169 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. For Product Information 1-800-833-0303 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 170 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 171 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 172 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 173 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 174 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 175 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 176 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 177 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 178 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 179 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 180 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 181 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 182 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 183 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 184 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 185 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 186 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 187 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 188 Baxter 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in AVIVA Plastic Container Description 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 220 mg Sodium Lactate (C3H5Na03), 205 mg Potassium Chloride, USP (KCl), 120 mg Sodium Chloride, USP (NaCl), and 100 mg Monobasic Potassium Phosphate, NF (KH2PO4). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). c D-Glucopyranose monohydrate 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 35 mEq potassium, 48 mEq chloride, 20 mEq lactate, and 15 mEq phosphate as HPO4 =. The osmolarity is 402 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOmsol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 189 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized in the liver to glycogen, and ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 190 dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overloading causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) may result in sodium or potassium retention. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 191 Carcinogenesis, mutagenesis, impairment of fertility Studies with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). It is also not known whether 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers IT IS NOT KNOWN WHETHER THIS DRUG IS EXCRETED IN HUMAN MILK. BECAUSE MANY DRUGS ARE EXCRETED IN HUMAN MILK, CAUTION SHOULD BE EXERCISED WHEN 5% DEXTROSE AND ELECTROLYTE NO. 75 INJECTION (MULTIPLE ELECTROLYTES AND DEXTROSE INJECTION, TYPE 3, USP) IS ADMINISTERED TO A NURSING MOTHER. Pediatric Use Safety and effectiveness of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 192 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2112 250 NDC 0338-6338-02 6E2113 500 NDC 0338-6338-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 193 6E2114 1000 NDC 0338-6338-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 194 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 195 Baxter 3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container Description 3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. The pH may have been adjusted with hydrochloric acid. It contains no antimicrobial agents. Composition, ionic concentration, osmolarity, and pH are shown in Table 1. Composition (g/L) Ionic Concentration (mEq/L) Table 1 size (mL) Sodium Chloride USP (NaCl) Sodium Chloride Osmolarity (mOsmol/L) (calc) pH 3% Sodium Chloride Injection, USP 500 30 513 513 1027 5.5 (4.5 to 7.0) 5% Sodium Chloride Injection, USP 500 50 856 856 1711 5.5 (4.5 to 7.0) Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 196 Clinical Pharmacology 3% and 5% Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage 3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings 3% and 5% Sodium Chloride Injection, USP is strongly hypertonic and may cause vein damage. 3% and 5% Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of 3% and 5% Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 197 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 3% and 5% Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with 3% and 5% Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 3% and 5% Sodium Chloride Injection, USP. It is also not known whether 3% and 5% Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 3% and 5% Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 3% and 5% Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 3% and 5% Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of 3% and 5% Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of 3% and 5% Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 198 Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied 3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows: Code Size (mL) NDC Product Name 6E1353 500 0338-6339-03 3% Sodium Chloride Injection, USP 6E1373 500 0338-6340-03 5% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 199 Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 200 Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 201 Baxter PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic, hypotonic solution in a single dose container for intravenous administration. Each 100 mL contains 234 mg of Sodium Chloride, USP (NaCl); 128 mg of Potassium Acetate, USP (C2H3KO2); and 32 mg of Magnesium Acetate Tetrahydrate (Mg(C2H3O2)2•4H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water and electrolytes. One liter has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The osmolarity is 111 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 202 PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of hemolysis. The intravenous administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 203 Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA- LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 204 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 205 All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2524 1000 NDC 0338-6341-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 206 To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 207 Baxter Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown below: Composition (g/L) Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added Size (mL) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Lactate, (C3H5NaO3) Potassium Chloride, USP (KCl) Calcium Chloride, USP (CaCl2•2H2O) Osmolarity (mOsmol/L) (calc.) 20 mEq 1000 50 6 3.1 1.79 0.2 565 40 mEq 1000 50 6 3.1 3.28 0.2 605 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 208 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Ionic Concentration (mEq/L) Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added pH Sodium Potassium Calcium Chloride Lactate Caloric Content (kcal/L) 20 mEq 5.0 (3.5 to 6.5) 130 24 3 129 28 170 40 mEq 5.0 (3.5 to 6.5) 130 44 3 149 28 170 ** The chemical structure for Dextrose Hydrous, USP is shown below: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 209 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of water, electrolytes, and calories or as alkalinizing agents. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn product. Warnings Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 210 congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are not for use in the treatment of lactic acidosis. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution. Excess administration may result in metabolic alkalosis. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 211 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose in prescribed to pediatric patients, particularly neonates and low birth weight infants. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Geriatric Use Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 212 from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of final filter is recommended during administration of fall parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size (mL) NDC Product Name 6E2224 1000 NDC 0338-6344-04 20 mEq/L Potassium Chloride in Lactated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 213 Ringer’s and 5% Dextrose Injection, USP 6E2244 1000 NDC 0338-6345-04 40 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 214 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:02.817674	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/013684s092,016677s139,et al_lbl.pdf', 'application_number': 16677, 'submission_type': 'SUPPL ', 'submission_number': 139}
10,912	07-19-70-016 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH nominal (range) Ionic Concentration (mEq/L) Caloric Content (kcal/L) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda supplemental medication (See DIRECTIONS FOR USE). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo – or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral oedema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% Sodium Chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. 6 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 500 0338-6315-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1024 1000 0338-6315-04 6E1092 250 0338-6310-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1093 500 0338-6310-03 6E1094 1000 0338-6310-04 6E1082 250 0338-6309-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1083 500 0338-6309-03 6E1084 1000 0338-6309-04 6E1072 250 0338-6308-02 5% Dextrose and 0.45% Sodium Chloride Reference ID: 3370954 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Injection, USP 6E1073 500 0338-6308-03 6E1074 1000 0338-6308-04 6E1062 250 0338-6305-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1063 500 0338-6305-03 6E1064 1000 0338-6305-04 6E1163 500 0338-6314-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1164 1000 0338-6314-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071970016 07-19-70-016 Rev. September 2013 Baxter and AVIVA are trademarks of Baxter International Inc. Reference ID: 3370954 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-70-015 Baxter Dextrose and Sodium Chloride Injection, USP in VIAFLEX Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1. Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH Ionic Concentration (mEq/L) Caloric Content (kcal/L) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo– or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% sodium chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Do not administer unless solution is clear and seal is intact. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Reference ID: 3370954 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in VIAFLEX plastic container is supplied as follows: Code Size (mL) NDC Product Name 2B1023 500 0338-0073-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1024 1000 0338-0073-04 2B1092 250 0338-0077-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 2B1093 500 0338-0077-03 2B1094 1000 0338-0077-04 2B1082 250 0338-0081-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 2B1083 500 0338-0081-03 2B1084 1000 0338-0081-04 2B1072 250 0338-0085-02 5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1073 500 0338-0085-03 2B1074 1000 0338-0085-04 2B1062 250 0338-0089-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1063 500 0338-0089-03 2B1064 1000 0338-0089-04 2B1163 500 0338-0095-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1164 1000 0338-0095-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER 7 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication WARNING Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *For Bar Code Position Only 071970015 07-19-70-15 Rev. September 2013 07-19-70-16 BAXTER, VIAFLEX and PL 146 are trademarks of Baxter International Inc. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:02.922973	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016678s105,016697s096,016689s105,016696s097,016683s100,016687s102lbl.pdf', 'application_number': 16687, 'submission_type': 'SUPPL ', 'submission_number': 102}
10,913	07-19-70-016 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH nominal (range) Ionic Concentration (mEq/L) Caloric Content (kcal/L) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda supplemental medication (See DIRECTIONS FOR USE). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo – or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral oedema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% Sodium Chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. 6 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 500 0338-6315-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1024 1000 0338-6315-04 6E1092 250 0338-6310-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1093 500 0338-6310-03 6E1094 1000 0338-6310-04 6E1082 250 0338-6309-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1083 500 0338-6309-03 6E1084 1000 0338-6309-04 6E1072 250 0338-6308-02 5% Dextrose and 0.45% Sodium Chloride Reference ID: 3370954 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Injection, USP 6E1073 500 0338-6308-03 6E1074 1000 0338-6308-04 6E1062 250 0338-6305-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1063 500 0338-6305-03 6E1064 1000 0338-6305-04 6E1163 500 0338-6314-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1164 1000 0338-6314-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071970016 07-19-70-016 Rev. September 2013 Baxter and AVIVA are trademarks of Baxter International Inc. Reference ID: 3370954 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-70-015 Baxter Dextrose and Sodium Chloride Injection, USP in VIAFLEX Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1. Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH Ionic Concentration (mEq/L) Caloric Content (kcal/L) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo– or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% sodium chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Do not administer unless solution is clear and seal is intact. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Reference ID: 3370954 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in VIAFLEX plastic container is supplied as follows: Code Size (mL) NDC Product Name 2B1023 500 0338-0073-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1024 1000 0338-0073-04 2B1092 250 0338-0077-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 2B1093 500 0338-0077-03 2B1094 1000 0338-0077-04 2B1082 250 0338-0081-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 2B1083 500 0338-0081-03 2B1084 1000 0338-0081-04 2B1072 250 0338-0085-02 5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1073 500 0338-0085-03 2B1074 1000 0338-0085-04 2B1062 250 0338-0089-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1063 500 0338-0089-03 2B1064 1000 0338-0089-04 2B1163 500 0338-0095-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1164 1000 0338-0095-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER 7 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication WARNING Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *For Bar Code Position Only 071970015 07-19-70-15 Rev. September 2013 07-19-70-16 BAXTER, VIAFLEX and PL 146 are trademarks of Baxter International Inc. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:02.932181	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016678s105,016697s096,016689s105,016696s097,016683s100,016687s102lbl.pdf', 'application_number': 16689, 'submission_type': 'SUPPL ', 'submission_number': 105}
10,911	07-19-63-782 Baxter Lactated Ringer’s and 5% Dextrose Injection, USP in VIAFLEX Plastic Container DESCRIPTION Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 600 mg Sodium Chloride, USP (NaCl); 310 mg Sodium Lactate (C3H5NaO3); 30 mg of Potassium Chloride, USP (KCl); and 20 mg Calcium Chloride, USP (CaCl2 • 2H20). It contains no antimicrobial agents. Approximate pH 5.0 (4.0 to 6.5). structural formula Lactated Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 130 mEq sodium, 4 mEq potassium, 2.7 mEq calcium, 109 mEq chloride and 28 mEq lactate. The osmolarity is 525 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. The caloric content is 180 kcal/L. The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Lactated Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s and 5% Dextrose Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Lactated Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. CONTRAINDICATIONS As for other calcium-containing infusion solutions, concomitant administration of ceftriaxone and Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in newborns (≤ 28 days of age), even if separate infusion lines are used (risk of fatal ceftriaxone-calcium salt precipitation in the neonate’s bloodstream). In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including Lactated Ringer’s and 5% Dextrose Injection, USP, through the same infusion line (e.g., via Y- connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed between infusions with a compatible fluid. Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. WARNINGS Although Lactated Ringer’s and 5% Dextrose Injection, USP has a potassium concentration similar to the concentration in plasma, it is insufficient to produce a useful effect in case of severe potassium deficiency; therefore, it should not be used for this purpose. 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactated Ringer’s and 5% Dextrose Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with citrate anticoagulated/preserved blood through the same administration set because of the likelihood of coagulation. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Hypersensitivity reactions are reported more frequently during pregnancy. Solutions containing dextrose should be used with caution, if at all, in patients with known allergy to corn or corn products. Depending on the volume and rate of infusion, the intravenous administration of Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid-base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with hyperkalemia or conditions predisposing to hyperkalemia (such as severe renal impairment or adrenocortical insufficiency, acute dehydration, or extensive tissue injury or burns) and in patients with cardiac disease. Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda overhydration, or conditions that may cause sodium and/or potassium retention, fluid overload, or edema. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactate is a substrate for gluconeogenesis. Administration of solutions containing dextrose and lactate should be used with caution in patients with impaired glucose tolerance and diabetes mellitus, as it may result in hyperglycemia. Hyperglycemia has been implicated in increasing cerebral ischemic brain damage and impairing recovery after acute ischemic strokes. Caution is recommended in using dextrose-containing solutions is such patients. Early hyperglycemia has been associated with poor outcomes in patients with severe traumatic brain injury. Dextrose-containing solutions should, therefore, be used with caution in patients with head injury, in particular during the first 24 hours following the trauma. If hyperglycemia occurs, the rate of dextrose administration should be reduced and/or insulin administered, or the insulin dose adjusted. Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia (i.e., high lactose levels) can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Lactated Ringer’s and 5% Dextrose Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The osmolarity of Lactated Ringer’s and 5% Dextrose Injection, USP is 525 mOsmol/L (calc). Administration of substantially hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. Solutions containing calcium salts should be used with caution in patients with hypercalcemia or conditions predisposing to hypercalemia, such as patients with severe renal impairment and granulomatous diseases associated with increased calcitriol synthesis such as sarcoidosis, calcium renal calculi or history of such calculi. Pediatric Use Safety and effectiveness of Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of lactated ringer’s and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In newborns, the risk of hyperglycemia due to infusion of dextrose-containing solutions appears to be greater with lower birth weight. In these patients, hyperglycemia and increased serum osmolarity have been associated with an increased risk of intraventricular cerebral hemorrhage. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. Geriatric Use Clinical studies of Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Ceftriaxone – see Contraindications Caution is advised when administering Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Lactated Ringer’s and 5% Dextrose Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine) and dextroamphetamine (dexamphetamine) sulfate, may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with lithium. Because of its potassium content, Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with caution in patients treated with agents or products that can cause hyperkalemia or increase the risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Caution is advised when administering Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with thiazide diuretics or vitamin D, as these can increase the risk of hypercalcemia. Pregnancy Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. For Hypersensitivity Reactions During Pregnancy – see Warnings 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, impairment of fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Lactated Ringer’s and 5% Dextrose Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer’s and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions, including anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, nausea and pyrexia. General Disorders and Administration Site Conditions: Infusion site reactions, including infusion site pruritus, infusion site erythema, infusion site anesthesia (numbness). Class Reactions -Other manifestations of hypersensitivity/infusion reactions: decreased heart rate, tachycardia, blood pressure decreased, respiratory distress, laryngeal edema, flushing, throat irritation, paresthesias, hypoesthesia oral, dysgeusia, anxiety, headache, and sneezing -Hyperkalemia -Hypervolemia 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda -Other infusion site reactions: infection at the site of injection, phlebitis, extravasation, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pain, infusion site burning. Overdose An excessive volume or too high a rate of administration of Lactated Ringer’s and 5% Dextrose Injection, USP may lead to fluid and sodium overload with a risk of edema (pheripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. Excessive administration of potassium may lead to the development of hyperkalemia, especially in patients with severe renal impairment. Excessive administration of calcium salts may lead to hypercalcemia. Excessive administration of a dextrose-containing solution may lead to hyperglycemia, hyperosmolarity, osmotic diuresis, and dehydration. When assessing overdose, any additives in the solution must also be considered. The effects of overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate, and duration of administration are to be individualized and dependent upon the indication for use, the patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. The infusion rate should not exceed the patient’s ability to utilize glucose in order to avoid hyperglycemia. 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. See Precautions, Pediatric Use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and the seal is intact. When making additions to Lactated Ringer’s and 5% Dextrose Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Lactated Ringer’s and 5% Dextrose Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Lactated Ringer’s and 5% Dextrose Injection, USP is appropriate. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Lactated Ringer’s and 5% Dextrose Injection, USP in VIAFLEX plastic containers is available as follows: Code Size NDC 2B2073 500 mL NDC 0338-0125-03 2B2074 1000 mL NDC 0338-0125-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. 9 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Directions for use of VIAFLEX plastic container For Information on Risk of Air Embolism - see Precautions To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 10 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071963782 07-19-63-782 Rev. October 2011 Baxter, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 11 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-63-783 Baxter Lactated Ringer’s Injection, USP in VIAFLEX Plastic Container DESCRIPTION Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Composition (g/L) Ionic Composition (mEq/L) Caloric Content (kcal/L) Size (mL) Sodium Chloride, USP, (NaCl) Sodium Lactate, (C3H5 NaO3 ) Potassium Chloride, USP, (KCl) Calcium Chloride, USP (CaCl2•2H2O) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride Lactate Lactated 250 6 3.1 0.3 0.2 273 6.5 (6.0 to 7.5) 130 4 2.7 109 28 9 Ringer’s 500 Injection, USP 1000 The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing agent. CONTRAINDICATIONS As for other calcium-containing infusion solutions, concomitant administration of ceftriaxone and Lactated Ringer’s Injection, USP is contraindicated in newborns (≤ 28 days of age), even if separate infusion lines are used (risk of fatal ceftriaxone-calcium salt precipitation in the neonate’s bloodstream). In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including Lactated Ringer’s Injection, USP, through the same infusion line (e.g., via Y-connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed between infusions with a compatible fluid. Lactated Ringer’s Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. WARNINGS Although Lactated Ringer’s Injection, USP has a potassium concentration similar to the concentration in plasma, it is insufficient to produce a useful effect in case of severe potassium deficiency; therefore, it should not be used for this purpose. Lactated Ringer’s Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. Lactated Ringer’s Injection, USP should not be administered simultaneously with citrate anticoagulated/preserved blood through the same administration set because of the likelihood of coagulation. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda instituted as clinically indicated. Hypersensitivity reactions are reported more frequently during pregnancy. Depending on the volume and the rate of infusion, the intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid-base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with hyperkalemia or conditions predisposing to hyperkalemia (such as severe renal impairment or adrenocortical insufficiency, acute dehydration, or extensive tissue injury or burns) and in patients with cardiac disease. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, overhydration, or conditions that may cause sodium and/or potassium retention, fluid overload, or edema. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Lactated Ringer’s Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. Solutions containing calcium salts should be used with caution in patients with hypercalcemia or conditions predisposing to hypercalemia, such as patients with severe renal impairment and granulomatous diseases associated with increased calcitriol synthesis such as sarcoidosis, calcium renal calculi or history of such calculi. Lactate is a substrate for gluconeogenesis. This should be taken into account when Lactated Ringer’s Injection, USP is used in patients with type 2 diabetes. Pediatric Use Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. Geriatric Use Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Ceftriaxone – see Contraindications Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Lactated Ringer’s Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine) and dextroamphetamine (dexamphetamine) sulfate, may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with lithium. Because of its potassium content, Lactated Ringer’s Injection, USP should be administered with caution in patients treated with agents or products that can cause hyperkalemia or increase risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with thiazide diuretics or vitamin D, as these can increase the risk of hypercalcemia. Pregnancy Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. For Hypersensitivity Reactions During Pregnancy – see Warnings 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, impairment of fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Lactated Ringer’s Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s Injection, USP is administered to a nursing mother. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions, including anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, decreased heart rate, tachycardia, blood pressure decreased, respiratory distress, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, flushing, throat irritation, paresthesias, hypoesthesia oral, dysgeusia, nausea, anxiety, pyrexia, headache Metabolism and Nutrition Disorders: Hyperkalemia General Disorders and Administration Site Conditions: Infusion site reactions, including phlebitis, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pruritus, infusion site erythema, infusion site pain, infusion site burning 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Class Reactions Hypersensitivity reactions, including, laryngeal edema and sneezing Hypervolemia Infusion site reactions, including Infection at the site of injection, extravasation, and infusion site anesthesia (numbness) Overdose An excessive volume or too high a rate of administration of Lactated Ringer’s Injection, USP may lead to fluid and sodium overload with a risk of edema (peripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. Excessive administration of potassium may lead to the development of hyperkalemia, especially in patients with severe renal impairment. Excessive administration of calcium salts may lead to hypercalcemia. When assessing an overdose, any additives in the solution must also be considered. The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate and duration of administration are to be individualized and dependent upon the indication for use, the patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and seal is intact. When making additions to Lactated Ringer’s Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Lactated Ringer’s Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Lactated Ringer’s Injection, USP is appropriate. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Lactated Ringer’s Injection, USP in VIAFLEX plastic container is available as follows: Code Size (mL) NDC 2B2322 250 0338-0117-02 2B2323 500 0338-0117-03 2B2324 1000 0338-0117-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER For Information on Risk of Air Embolism – see Precautions To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 9 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071963783 07-19-63-783 Rev. October 2011 BAXTER, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 10 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-63-784 Baxter Lactated Ringer’s Injection, USP in AVIVA Plastic Container DESCRIPTION Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc) pH nominal (range) Ionic Concentration (mEq/L) Caloric Content (kcal/L) Sodium Chloride, USP, (NaCl) Sodium Lactate, (C3 H5 NaO3 ) Potassium Chloride, USP, (KCl) Calcium Chloride, USP (CaCl2 ·2H2O) Sodium Potassium Calcium Chloride Lactate Lactated Ringer’s Injection, USP 250 6 3.1 0.3 0.2 273 6.5 (6.0 to 7.5) 130 4 2.7 109 28 9 500 1000 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing agent. CONTRAINDICATIONS As for other calcium-containing infusion solutions, concomitant administration of ceftriaxone and Lactated Ringer’s Injection, USP is contraindicated in newborns (≤ 28 days of age), even if separate infusion lines are used (risk of fatal ceftriaxone-calcium salt precipitation in the neonate’s bloodstream). In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including Lactated Ringer’s Injection, USP, through the same infusion line (e.g., via Y-connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed between infusions with a compatible fluid. 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactated Ringer’s Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. WARNINGS Although Lactated Ringer’s Injection, USP has a potassium concentration similar to the concentration in plasma, it is insufficient to produce a useful effect in case of severe potassium deficiency; therefore, it should not be used for this purpose. Lactated Ringer’s Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. Lactated Ringer’s Injection, USP should not be administered simultaneously with citrate anticoagulated/preserved blood through the same administration set because of the likelihood of coagulation. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Hypersensitivity reactions are reported more frequently during pregnancy. Depending on volume and rate of infusion, the intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid-base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with hyperkalemia or conditions predisposing to hyperkalemia (such as severe renal impairment or adrenocortical insufficiency, acute dehydration, or extensive tissue injury or burns) and in patients with cardiac disease. 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, overhydration, or conditions that may cause sodium and/or potassium retention, fluid overload, or edema. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Lactated Ringer’s Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. Solutions containing calcium salts should be used with caution in patients with hypercalcemia or conditions predisposing to hypercalemia, such as patients with severe renal impairment and granulomatous diseases associated with increased calcitriol synthesis such as sarcoidosis, calcium renal calculi or history of such calculi. Lactate is a substrate for gluconeogenesis. This should be taken into account when Lactated Ringer’s Injection, USP is used in patients with type 2 diabetes. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. Geriatric Use Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Drug Interactions Ceftriaxone – see Contraindications Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Lactated Ringer’s Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine) and dextroamphetamine (dexamphetamine) sulfate, may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with lithium. 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Because of its potassium content, Lactated Ringer’s Injection, USP should be administered with caution in patients treated with agents or products that can cause hyperkalemia or increase risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with thiazide diuretics or vitamin D, as these can increase the risk of hypercalcemia. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Lactated Ringer’s Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. For Hypersensitivity Reactions During Pregnancy – see Warnings Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Lactated Ringer’s Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s Injection, USP is administered to a nursing mother. ADVERSE REACTIONS 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions, including anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, decreased heart rate, tachycardia, blood pressure decreased, respiratory distress, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, flushing, throat irritation, paresthesias, hypoesthesia oral, dysgeusia, nausea, anxiety, pyrexia, headache Metabolism and Nutrition Disorders: Hyperkalemia General Disorders and Administration Site Conditions: Infusion site reactions, including phlebitis, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pruritus, infusion site erythema, infusion site pain, infusion site burning Class Reactions Hypersensitivity reactions, including, laryngeal edema and sneezing Hypervolemia Infusion site reactions, including Infection at the site of injection, extravasation, and infusion site anesthesia (numbness) Overdose An excessive volume or too high a rate of administration of Lactated Ringer’s Injection, USP may lead to fluid and sodium overload with a risk of edema (peripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. Excessive administration of potassium may lead to the development of hyperkalemia, especially in patients with severe renal impairment. Excessive administration of calcium salts may lead to hypercalcemia. When assessing an overdose, any additives in the solution must also be considered. 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate, and duration of administration are to be individualized and dependent upon the indication for use, the patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in AVIVA plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and seal is intact. When making additions to Lactated Ringer’s Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Lactated Ringer’s Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Lactated Ringer’s Injection, USP is appropriate. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Lactated Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2322 250 0338-6307-02 6E2323 500 0338-6307-03 6E2324 1000 0338-6307-04 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER For Information on Risk of Air Embolism – see Precautions To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 9 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071963784 07-19-63-784 Rev. October 2011 Baxter and AVIVA are trademarks of Baxter International Inc. 10 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-63-785 Baxter Sodium Lactate Injection, USP (M/6 Sodium Lactate) in VIAFLEX Plastic Container DESCRIPTION Sodium Lactate Injection, USP (M/6 Sodium Lactate) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with lactic acid. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc) pH Ionic Concentration (mEq/L) Caloric Content (kcal/L) Sodium Lactate (C3H5NaO3) Sodium Lactate Sodium Lactate Injection, USP (M/6 Sodium Lactate) 500 18.7 334 6.5 (6.0 to 7.3) 167 167 54 1000 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Sodium Lactate Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Sodium Lactate Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Sodium Lactate Injection, USP is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. CONTRAINDICATIONS Sodium Lactate Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. WARNINGS Sodium Lactate Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Depending on the volume and rate of infusion, the intravenous administration of these injections can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid- base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Excessive administration of Sodium Lactate Injection, USP may result in hypokalemia. 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sodium Lactate Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Sodium Lactate Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, overhydration, or conditions that may cause sodium retention, fluid overload, or edema. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Sodium Lactate Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Sodium Lactate Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. Lactate is a substrate for gluconeogenesis. This should be taken into account when Sodium Lactate Injection, USP is used in patients with type 2 diabetes. Pediatric Use Safety and effectiveness of Sodium Lactate Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium lactate solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use Clinical studies of Sodium Lactate Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Drug Interactions Caution is advised when administering Sodium Lactate Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Sodium Lactate Injection USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Sodium Lactate Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine), and dextroamphetamine (dexamphetamine) sulfate may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Sodium Lactate Injection, USP to patients treated with lithium. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Sodium Lactate Injection, USP. It is also not known whether Sodium Lactate Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Lactate Injection, USP should be given to a pregnant woman only if clearly needed. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Sodium Lactate Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Lactate Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Lactate Injection, USP is administered to a nursing mother. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions manifested by: blood pressure decreased, pyrexia General Disorders and Administration Site Conditions: Infusion site burning Class Reactions Other symptoms of hypersensitivity/infusion reactions: anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, decreased heart rate, tachycardia, respiratory distress, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, flushing, throat irritation, paresthaesias, hypesthesia oral, dysgeusia, nausea, anxiety and headache. Hypervolemia Infusion site reactions, including infection at the site of injection, phlebitis, extravasation, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pruritus, infusion site erythema, infusion site pain, infusion site anesthesia (numbness) 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Overdose An excessive volume or too high a rate of administration of Sodium Lactate Injection, USP may lead to fluid and sodium overload with a risk of edema (pheripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. When assessing an overdose, any additives in the solution must also be considered. The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate, and duration of administration are to be individualized and dependent upon the indication for use, patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and seal is intact. When making additions to Sodium Lactate Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Sodium Lactate Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Sodium Lactate Injection, USP is appropriate. 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Sodium Lactate Injection, USP (M/6 Sodium Lactate) in VIAFLEX plastic container is available as follows: Code Size (mL) NDC 2B1803 500 0338-0129-03 2B1804 1000 0338-0129-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER For Information on Risk of Air Embolism – see Precautions To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only 071963785 07-19-63-785 Rev. October 2011 BAXTER, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-63-786 Baxter Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in Plastic Container VIAFLEX Plus Container DESCRIPTION Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown below: Table 1. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Lactate, (C3H5 NaO3 ) Potassium Chloride, USP (KCl) Calcium Chloride, USP (CaCl2-2H2 O) 20 mEq 1000 50 6 3.1 1.79 0.2 565 40 mEq 1000 50 6 3.1 3.28 0.2 605 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added pH Ionic Concentration (mEq/L) Caloric Content (kcal/L) Sodium Potassium Calcium Chloride Lactate 20 mEq 5.0 (3.5 to 6.5) 130 24 3 129 28 170 40 mEq 5.0 (3.5 to 6.5) 130 44 3 149 28 170 The VIAFLEX Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). VIAFLEX Plus on the container indicates the presence of a drug additive in a drug vehicle. The VIAFLEX Plus plastic container system utilizes the same container as the VIAFLEX plastic container system. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2- ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of water, electrolytes, and calories or as alkalinizing agents. 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS As for other calcium-containing infusion solutions, concomitant administration of ceftriaxone and Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in newborns (≤ 28 days of age), even if separate infusion lines are used (risk of fatal ceftriaxone-calcium salt precipitation in the neonate’s bloodstream). In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including Potasssium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP, through the same infusion line (e.g., via Y-connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed between infusions with a compatible fluid. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in patients with hyperkalemia. WARNINGS Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with citrate anticoagulated/preserved blood through the same administration set because of the likelihood of coagulation. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Solutions containing dextrose should be used with caution, if at all, in patients with known allergy to corn or corn products. Depending on the volume and rate of infusion, the intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid-base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with conditions predisposing to hyperkalemia (such as severe renal impairment or adrenocortical insufficiency, acute dehydration, or extensive tissue injury or burns), in patients with cardiac disease, and in patients treated with products that increase the risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, overhydration, or conditions that may cause sodium and/or potassium retention, fluid overload, or edema. Potassium salts should never be administered by IV push. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactate is a substrate for gluconeogenesis. Administration of solutions containing dextrose and lactate should be used with caution in patients with impaired glucose tolerance and diabetes mellitus, as it may result in hyperglycemia. Hyperglycemia has been implicated in increasing cerebral ischemic brain damage and impairing recovery after acute ischemic strokes. Caution is recommended in using dextrose-containing solutions in such patients. Early hyperglycemia has been associated with poor outcomes in patients with severe traumatic brain injury. Dextrose-containing solutions should, therefore, be used with caution in patients with head injury, in particular during the first 24 hours following the trauma. If hyperglycemia occurs, the rate of dextrose administration should be reduced and/or insulin administered, or the insulin dose adjusted. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia (i.e., high lactate levels) can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. The osmolarity of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is 565 mOsmol/L (calc) for 20 mEq potassium added and 605 mOsmol/L (calc) for 40 mEq potassium added. Administration of substantially hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. Solutions containing calcium salts should be used with caution in patients with hypercalcemia or conditions predisposing to hypercalemia, such as patients with severe renal impairment and granulomatous diseases associated with increased calcitriol synthesis such as sarcoidosis, calcium renal calculi or history of such calculi. 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well- controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. In newborns, the risk of hyperglycemia due to infusion of dextrose-containing solutions appears to be greater with lower birth weight. In these patients, hyperglycemia and increased serum osmolarity have been associated with an increased risk of intraventricular cerebral hemorrhage. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. Geriatric Use Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Drug Interactions Ceftriaxone – see Contraindications Caution is advised when administering Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine) and dextroamphetamine (dexamphetamine) sulfate, may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with lithium. Because of its potassium content, administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be avoided in patients treated with agents or products that can cause hyperkalemia or increase the risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Administration of potassium in patients treated with such medications can produce severe and potentially fatal hyperkalemia, particularly in patients with severe renal insufficiency. Caution is advised when administering Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with thiazide diuretics or vitamin D, as these can increase the risk of hypercalcemia. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions, including anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, nausea and pyrexia. General Disorders and Administration Site Conditions: Infusion site reactions, including infusion site pruritus, infusion site erythema, infusion site anesthesia (numbness). Class Reactions -Other manifestations of hypersensitivity/infusion reactions: decreased heart rate, tachycardia, blood pressure decreased, respiratory distress, flushing, throat irritation, paresthesias, hypoesthesia oral, dysgeusia, anxiety and headache -Hyperkalemia -Hypervolemia -Other infusion site reactions: infection at the site of injection, phlebitis, extravasation, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pain, infusion site burning Overdose An excessive volume or too high a rate of administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may lead to fluid and sodium 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda overload with a risk of edema (pheripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. Excessive administration of potassium may lead to the development of hyperkalemia, especially in patients with severe renal impairment. Excessive administration of calcium salts may lead to hypercalcemia. Excessive administration of a dextrose-containing solution may lead to hyperglycemia, hyperosmolarity, osmotic diuresis, and dehydration. When assessing overdose, any additives in the solution must also be considered. The effects of overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate, and duration of administration are to be individualized and dependent upon the indication for use, the patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in VIAFLEX Plus plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. The infusion rate should not exceed the patient’s ability to utilize glucose in order to avoid hyperglycemia. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. See Precautions, Pediatric Use. 9 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and the seal is intact. When making additions to Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is appropriate. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in VIAFLEX Plus plastic containers is available as shown below: Code Size (mL) NDC Product Name 2B2224 1000 0338-0811-04 20 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP 2B2244 1000 0338-0815-04 40 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER For Information on Risk of Air Embolism – see Precautions 10 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 11 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *Bar Code Position Only 071963786 07-19-63-786 Revised October 2011 Baxter, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. Reference ID: 3028897 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.193814	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016679s104,016682s105,016692s095,019367s026lbl.pdf', 'application_number': 16679, 'submission_type': 'SUPPL ', 'submission_number': 104}
10,916	07-19-70-016 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH nominal (range) Ionic Concentration (mEq/L) Caloric Content (kcal/L) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda supplemental medication (See DIRECTIONS FOR USE). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo – or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral oedema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% Sodium Chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. 6 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 500 0338-6315-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1024 1000 0338-6315-04 6E1092 250 0338-6310-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1093 500 0338-6310-03 6E1094 1000 0338-6310-04 6E1082 250 0338-6309-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1083 500 0338-6309-03 6E1084 1000 0338-6309-04 6E1072 250 0338-6308-02 5% Dextrose and 0.45% Sodium Chloride Reference ID: 3370954 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Injection, USP 6E1073 500 0338-6308-03 6E1074 1000 0338-6308-04 6E1062 250 0338-6305-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1063 500 0338-6305-03 6E1064 1000 0338-6305-04 6E1163 500 0338-6314-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1164 1000 0338-6314-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071970016 07-19-70-016 Rev. September 2013 Baxter and AVIVA are trademarks of Baxter International Inc. Reference ID: 3370954 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-70-015 Baxter Dextrose and Sodium Chloride Injection, USP in VIAFLEX Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1. Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH Ionic Concentration (mEq/L) Caloric Content (kcal/L) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo– or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% sodium chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Do not administer unless solution is clear and seal is intact. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Reference ID: 3370954 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in VIAFLEX plastic container is supplied as follows: Code Size (mL) NDC Product Name 2B1023 500 0338-0073-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1024 1000 0338-0073-04 2B1092 250 0338-0077-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 2B1093 500 0338-0077-03 2B1094 1000 0338-0077-04 2B1082 250 0338-0081-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 2B1083 500 0338-0081-03 2B1084 1000 0338-0081-04 2B1072 250 0338-0085-02 5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1073 500 0338-0085-03 2B1074 1000 0338-0085-04 2B1062 250 0338-0089-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1063 500 0338-0089-03 2B1064 1000 0338-0089-04 2B1163 500 0338-0095-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1164 1000 0338-0095-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER 7 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication WARNING Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *For Bar Code Position Only 071970015 07-19-70-15 Rev. September 2013 07-19-70-16 BAXTER, VIAFLEX and PL 146 are trademarks of Baxter International Inc. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.275147	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016678s105,016697s096,016689s105,016696s097,016683s100,016687s102lbl.pdf', 'application_number': 16697, 'submission_type': 'SUPPL ', 'submission_number': 96}
10,914	Ringer’s Injection, USP in VIAFLEX Plastic Container DESCRIPTION Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Table 1. Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc) pH Ionic Concentration (mEq/L) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2-2H2 O) Potassium Chloride, USP (KCl) Sodium Potassium Calcium Chloride Ringer’s Injection, USP 500 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 1000 The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Reference ID: 3923526 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Ringer’s Injection, USP is indicated as a source of water and electrolytes. CONTRAINDICATIONS Concomitant treatment with ceftriaxone and Ringer’s Injection, USP is contraindicated in newborns (≤28 days of age), even if separate infusion lines are used due to the risk of fatal ceftriaxone-calcium salt precipitation in the neonate’s bloodstream. WARNINGS Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. In patients older than 28 days, including adults, ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including Ringer’s Injection, USP, through the same infusion line (e.g., via a Y-connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed between infusions with a compatible fluid. Reference ID: 3923526 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Pediatric Use The use of Ringer’s Injection, USP in pediatric patients is based on clinical practice. Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater Reference ID: 3923526 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Do not administer unless solution is clear and seal is intact. Drug Interactions For information on the use of Ringer’s Injection, USP with ceftriaxone, see CONTRAINDICATIONS and WARNINGS sections. ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Ringer’s Injection, USP in VIAFLEX plastic container is available as follows: Code Size (mL) NDC 2B2303 500 0338-0105-03 2B2304 1000 0338-0105-04 Reference ID: 3923526 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication WARNING: Additives may be incompatible To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. Reference ID: 3923526 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA 07-19-73-751 Rev. October 2014 Baxter, Pl 146 and Viaflex are trademarks of Baxter International Inc. Reference ID: 3923526 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.335111	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016693s098lbl.pdf', 'application_number': 16693, 'submission_type': 'SUPPL ', 'submission_number': 98}
10,915	07-19-70-016 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH nominal (range) Ionic Concentration (mEq/L) Caloric Content (kcal/L) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda supplemental medication (See DIRECTIONS FOR USE). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. PRECAUTIONS General Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo – or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral oedema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% Sodium Chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. 6 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 500 0338-6315-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1024 1000 0338-6315-04 6E1092 250 0338-6310-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1093 500 0338-6310-03 6E1094 1000 0338-6310-04 6E1082 250 0338-6309-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1083 500 0338-6309-03 6E1084 1000 0338-6309-04 6E1072 250 0338-6308-02 5% Dextrose and 0.45% Sodium Chloride Reference ID: 3370954 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Injection, USP 6E1073 500 0338-6308-03 6E1074 1000 0338-6308-04 6E1062 250 0338-6305-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1063 500 0338-6305-03 6E1064 1000 0338-6305-04 6E1163 500 0338-6314-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1164 1000 0338-6314-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071970016 07-19-70-016 Rev. September 2013 Baxter and AVIVA are trademarks of Baxter International Inc. Reference ID: 3370954 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-70-015 Baxter Dextrose and Sodium Chloride Injection, USP in VIAFLEX Plastic Container DESCRIPTION Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1. Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) pH Ionic Concentration (mEq/L) Caloric Content (kcal/L) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Chloride 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 1 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 2 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. INDICATIONS AND USAGE Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. 3 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Administration of hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. See Table 1 in the DESCRIPTION section for the osmolarities of the Dextrose and Sodium Chloride Injection, USP solutions. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. 4 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also not known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Dextrose and Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Newborns – especially those born premature and with low birth weight – are at increased risk of developing hypo– or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency (applies to solutions containing less than 0.9% sodium chloride). Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond 5 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Do not administer unless solution is clear and seal is intact. ADVERSE REACTIONS - Hypersensitivity reactions, including anaphylaxis and chills - Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride) Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. The dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy. Additives may be incompatible. Complete information is not available. Reference ID: 3370954 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Dextrose and Sodium Chloride Injection, USP in VIAFLEX plastic container is supplied as follows: Code Size (mL) NDC Product Name 2B1023 500 0338-0073-03 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1024 1000 0338-0073-04 2B1092 250 0338-0077-02 5% Dextrose and 0.2% Sodium Chloride Injection, USP 2B1093 500 0338-0077-03 2B1094 1000 0338-0077-04 2B1082 250 0338-0081-02 5% Dextrose and 0.33% Sodium Chloride Injection, USP 2B1083 500 0338-0081-03 2B1084 1000 0338-0081-04 2B1072 250 0338-0085-02 5% Dextrose and 0.45% Sodium Chloride Injection, USP 2B1073 500 0338-0085-03 2B1074 1000 0338-0085-04 2B1062 250 0338-0089-02 5% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1063 500 0338-0089-03 2B1064 1000 0338-0089-04 2B1163 500 0338-0095-03 10% Dextrose and 0.9% Sodium Chloride Injection, USP 2B1164 1000 0338-0095-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER 7 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication WARNING Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Reference ID: 3370954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *For Bar Code Position Only 071970015 07-19-70-15 Rev. September 2013 07-19-70-16 BAXTER, VIAFLEX and PL 146 are trademarks of Baxter International Inc. 9 Reference ID: 3370954 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.344707	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016678s105,016697s096,016689s105,016696s097,016683s100,016687s102lbl.pdf', 'application_number': 16696, 'submission_type': 'SUPPL ', 'submission_number': 97}
10,917	MEDICATION GUIDE Dalmane® (DAL-main) Capsules, 15 mg and 30 mg is a Sedative-Hypnotic indicated for Insomnia Generic name: flurazepam (flew-raz-e-pam) hydrochloride capsules only Read this Medication Guide carefully before you start taking your medicine and each time you get more, since there may be new information. It does not contain all the information about your medicine that you may need to know, so please ask your doctor, nurse or pharmacist if you have any questions. IMPORTANT YOUR DOCTOR HAS PRESCRIBED THIS DRUG FOR YOUR USE ONLY. DO NOT LET ANYONE ELSE USE IT. KEEP THIS MEDICINE OUT OF THE REACH OF CHILDREN AND PETS. If a child puts a Dalmane® capsule in his or her mouth or swallows it, call your local Poison Control Center or go immediately to the nearest emergency room. What is the most important information I should know about sedative- hypnotic drugs? After taking a sedative-hypnotic drug, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medications that make you sleepy with a sedative-hypnotic drug. Reported activities include: • driving a car ("sleep-driving") • making and eating food • talking on the phone • having sex • sleep-walking Important: 1. Take a sedative-hypnotic drug exactly as prescribed: • Do not take more sedative-hypnotic drugs than prescribed. • Take the sedative-hypnotic drug right before you get in bed, not sooner. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Do not take a sedative-hypnotic drug if you: • drink alcohol • take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take a sedative- hypnotic drug with your other medicines • cannot get a full night sleep 3. Call your doctor right away if you find out that you have done any of the above activities after taking a sedative-hypnotic drug. What is Dalmane®? Dalmane® is a sedative-hypnotic agent used to treat insomnia (difficulty falling asleep and staying asleep). Who should not take Dalmane®? Do not use Dalmane® if you are: • allergic to anything in Dalmane®. (Being allergic may include having a rash, itching, swelling or breathing difficulties.) See the end of this Medication Guide for a complete list of ingredients in Dalmane®. In rare cases patient have had additional symptoms such as shortness of breath, throat closing, or nausea and vomiting that suggest an allergic reaction. Some patients have required medical therapy in the emergency department as these rare complications could be fatal. Patients who experience these symptoms should seek medical attention and discontinue taking the sedative-hypnotic drug. • pregnant or intending to become pregnant. If a woman becomes pregnant while taking Dalmane®, she should discontinue use immediately. • under 15 years of age. Dalmane® has not been studied in children. How should I take Dalmane®? Dalmane® comes as a capsule to take by mouth. You should take Dalmane®, or other sedative-hypnotic medications, exactly as directed by your doctor. It usually is taken right before you get in bed, not sooner. If you forget to take Dalmane® at bedtime, you are unable to fall asleep, and you will still be able to stay in bed for a full night’s sleep, you may take Dalmane® at that time. Do not take a double dose of Dalmane® to make up for a missed dose. The smallest possible effective dose is suggested for elderly patients due to the risk of the development of oversedation, dizziness, confusion and/or loss of coordination. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sleep problems are often temporary, requiring treatment for a very short time. You should not use Dalmane®, or any other sedative-hypnotic medications, for long periods of time without talking to your doctor about the risks and benefits of prolonged use. In the case of a suspected overdose, you should contact your local poison control center immediately. What should I avoid while taking Dalmane®? Do not drink alcohol or take other medications that depress the central nervous system. While taking Dalmane®, do not engage in any hazardous occupations requiring complete mental alertness such as operating machinery or driving a car. What are the possible or reasonably likely side effects of Dalmane®? Dizziness, drowsiness, light-headedness, staggering, loss of coordination and falling have occurred, particularly in elderly or debilitated persons. Severe sedation, lethargy, disorientation and coma, probably indicative of drug intolerance or overdosage, have been reported. Also reported are headache, heartburn, upset stomach, nausea, vomiting, diarrhea, constipation, nervousness, talking more than usual, anxiety, irritability, weakness, pounding heartbeat, chest pain, body and joint pains and difficulty urinating. General information about the safe and effective use of Dalmane® Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you have any concerns about taking this, or any sedative- hypnotic medication, please ask your doctor. For detailed information regarding Dalmane® please consult the physician’s package insert. Do not use for conditions for which this medication was not prescribed. Do not give this medication to others. What are the ingredients of Dalmane® Capsules? Active Ingredient: flurazepam hydrochloride (15 mg or 30 mg) Inactive Ingredients: Each 15 mg capsule also contains cornstarch, lactose, magnesium stearate and talc; gelatin capsule shells contain D&C Red No. 28, FD&C Red No. 40, FD&C Yellow No. 6 and D&C Yellow No. 10. Each 30 mg capsule also contains cornstarch, lactose and magnesium stearate; gelatin capsule shells contain FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 and either FD&C Red No. 3 or FD&C Red No. 40. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How should I store Dalmane® Capsules? • Store Dalmane® Capsules at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature]. • KEEP THIS MEDICINE OUT OF THE REACH OF CHILDREN. If a child accidentally takes Dalmane®, call your local Poison Control Center or go immediately to the nearest emergency room. This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: Valeant Pharmaceuticals North America Aliso Viejo, CA 92625 U.S.A. logo Part No.: XXXXXXXXX Rev. Date: 3/09 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------- --------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. /s/ Russell Katz 3/27/2009 12:42:58 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.494508	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016721s077lbl.pdf', 'application_number': 16721, 'submission_type': 'SUPPL ', 'submission_number': 77}
10,918	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.506930	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/16584s55s47lbl.pdf', 'application_number': 16758, 'submission_type': 'SUPPL ', 'submission_number': 17}
10,920	NAVANE® Thiothixene Capsules Thiothixene Hydrochloride Concentrate WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis— Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Navane is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Navane® (thiothixene) is a thioxanthene derivative. Specifically, it is the cis isomer of N,N dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene] thioxanthene-2-sulfonamide. structural e le ment The thioxanthenes differ from the phenothiazines by the replacement of nitrogen in the central ring with a carbon-linked side chain fixed in space in a rigid structural configuration. An N,N dimethyl sulfonamide functional group is bonded to the thioxanthene nucleus. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inert ingredients for the capsule formulations are: hard gelatin capsules (which contain gelatin and titanium dioxide; may contain Yellow 10, Yellow 6, Blue 1, Green 3, Red 3, and other inert ingredients); lactose; magnesium stearate; sodium lauryl sulfate; starch. Inert ingredients for the oral concentrate formulation are: alcohol; cherry flavor; dextrose; passion fruit flavor; sorbitol solution; water. ACTIONS Navane is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. INDICATIONS Navane is effective in the management of schizophrenia. Navane has not been evaluated in the management of behavioral complications in patients with mental retardation. CONTRAINDICATIONS Navane is contraindicated in patients with circulatory collapse, comatose states, central nervous system depression due to any cause, and blood dyscrasias. Navane is contraindicated in individuals who have shown hypersensitivity to the drug. It is not known whether there is a cross sensitivity between the thioxanthenes and the phenothiazine derivatives, but this possibility should be considered. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis— Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Navane is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Tardive Dyskinesia–Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene(1). Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to “Information for Patients” in the PRECAUTIONS section, and to the ADVERSE REACTIONS section.) Neuroleptic Malignant Syndrome (NMS)–A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene(2). Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usage in Pregnancy–Safe use of Navane during pregnancy has not been established. Therefore, this drug should be given to pregnant patients only when, in the judgment of the physician, the expected benefits from the treatment exceed the possible risks to mother and fetus. Animal reproduction studies and clinical experience to date have not demonstrated any teratogenic effects. In the animal reproduction studies with Navane, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. Similar findings have been reported with other psychotropic agents. After repeated oral administration of Navane to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen. Usage in Children–The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. As is true with many CNS drugs, Navane may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, especially during the first few days of therapy. Therefore, the patient should be cautioned accordingly. As in the case of other CNS-acting drugs, patients receiving Navane (thiothixene) should be cautioned about the possible additive effects (which may include hypotension) with CNS depressants and with alcohol. PRECAUTIONS An antiemetic effect was observed in animal studies with Navane; since this effect may also occur in man, it is possible that Navane may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor. In consideration of the known capability of Navane and certain other psychotropic drugs to precipitate convulsions, extreme caution should be used in patients with a history of convulsive disorders or those in a state of alcohol withdrawal, since it may lower the convulsive threshold. Although Navane potentiates the actions of the barbiturates, the dosage of the anticonvulsant therapy should not be reduced when Navane is administered concurrently. Though exhibiting rather weak anticholinergic properties, Navane should be used with caution in patients who might be exposed to extreme heat or who are receiving atropine or related drugs. Use with caution in patients with cardiovascular disease. Caution as well as careful adjustment of the dosages is indicated when Navane is used in conjunction with other CNS depressants. Also, careful observation should be made for pigmentary retinopathy and lenticular pigmentation (fine lenticular pigmentation has been noted in a small number of patients treated with Navane 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda for prolonged periods). Blood dyscrasias (agranulocytosis, pancytopenia, thrombocytopenic purpura), and liver damage (jaundice, biliary stasis) have been reported with related drugs. Antipsychotic drugs, including thiothixene(3), elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. Leukopenia, Neutropenia and Agranulocytosis: Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Navane should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Navane and have their WBC followed until recovery. Information for Patients: Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. Drug Interactions: Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness.(4,5) Due to a possible additive effect with hypotensive agents, patients receiving these drugs should be observed closely for signs of excessive hypotension when thiothixene is added to their drug regimen.(6) 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS NOTE: Not all of the following adverse reactions have been reported with Navane. However, since Navane has certain chemical and pharmacologic similarities to the phenothiazines, all of the known side effects and toxicity associated with phenothiazine therapy should be borne in mind when Navane is used. Cardiovascular Effects: Tachycardia, hypotension, lightheadedness, and syncope. In the event hypotension occurs, epinephrine should not be used as a pressor agent since a paradoxical further lowering of blood pressure may result. Nonspecific EKG changes have been observed in some patients receiving Navane. These changes are usually reversible and frequently disappear on continued Navane therapy. The incidence of these changes is lower than that observed with some phenothiazines. The clinical significance of these changes is not known. CNS Effects: Drowsiness, usually mild, may occur although it usually subsides with continuation of Navane therapy. The incidence of sedation appears similar to that of the piperazine group of phenothiazines but less than that of certain aliphatic phenothiazines. Restlessness, agitation and insomnia have been noted with Navane. Seizures and paradoxical exacerbation of psychotic symptoms have occurred with Navane infrequently. Hyperreflexia has been reported in infants delivered from mothers having received structurally related drugs. In addition, phenothiazine derivatives have been associated with cerebral edema and cerebrospinal fluid abnormalities. Extrapyramidal Symptoms Extrapyramidal symptoms, such as pseudoparkinsonism, akathisia and dystonia have been reported (see Dystonia, Class effect). Management of these extra-pyramidal symptoms depends upon the type and severity. Rapid relief of acute symptoms may require the use of an injectable antiparkinson agent. More slowly emerging symptoms may be managed by reducing the dosage of Navane and/or administering an oral antiparkinson agent. Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Persistent Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy with thiothixene(1) or may occur after drug therapy has been discontinued. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities. Since early detection of tardive dyskinesia is important, patients should be monitored on an ongoing basis. It has been reported that fine vermicular movement of the tongue may be an early sign of the syndrome. If this or any other presentation of the syndrome is observed, the clinician should consider possible discontinuation of antipsychotic medication. (See WARNINGS section.) Hepatic Effects: Elevations of serum transaminase and alkaline phosphatase, usually transient, have been infrequently observed in some patients. No clinically confirmed cases of jaundice attributable to Navane (thiothixene) have been reported. Hematologic Effects: As is true with certain other psychotropic drugs, leukopenia and leucocytosis, which are usually transient, can occur occasionally with Navane. Other antipsychotic drugs have been associated with agranulocytosis, eosinophilia, hemolytic anemia, thrombocytopenia and pancytopenia. Allergic Reactions: Rash, pruritus, urticaria, photosensitivity and rare cases of anaphylaxis have been reported with Navane. Undue exposure to sunlight should be avoided. Although not experienced with Navane, exfoliative dermatitis and contact dermatitis (in nursing personnel) have been reported with certain phenothiazines. Endocrine/Reproductive: Hyperprolactinemia(3); lactation, menstrual irregularities, moderate breast enlargement and amenorrhea have occurred in a small percentage of females receiving Navane. If persistent, this may necessitate a reduction in dosage or the discontinuation of therapy. Phenothiazines have been associated with false positive pregnancy tests, gynecomastia, hypoglycemia, hyperglycemia and glycosuria. Autonomic Effects: Dry mouth, blurred vision, nasal congestion, constipation, increased sweating, increased salivation and impotence have occurred infrequently with Navane therapy. Phenothiazines have been associated with miosis, mydriasis, and adynamic ileus. Other Adverse Reactions: Hyperpyrexia, anorexia, nausea, vomiting, diarrhea, increase in appetite and weight, weakness or fatigue, polydipsia, and peripheral edema. Although not reported with Navane, evidence indicates there is a relationship between phenothiazine therapy and the occurrence of a systemic lupus erythematosus-like syndrome. Neuroleptic Malignant Syndrome (NMS): Please refer to the text regarding NMS in the WARNINGS section. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOTE: Sudden deaths have occasionally been reported in patients who have received certain phenothiazine derivatives. In some cases the cause of death was apparently cardiac arrest or asphyxia due to failure of the cough reflex. In others, the cause could not be determined nor could it be established that death was due to phenothiazine administration. DOSAGE AND ADMINISTRATION Dosage of Navane should be individually adjusted depending on the chronicity and severity of the symptoms of schizophrenia. In general, small doses should be used initially and gradually increased to the optimal effective level, based on patient response. Some patients have been successfully maintained on once-a-day Navane therapy. The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. In milder conditions, an initial dose of 2 mg three times daily is recommended. If indicated, a subsequent increase to 15 mg/day total daily dose is often effective. In more severe conditions, an initial dose of 5 mg twice daily is recommended. The usual optimal dose is 20 to 30 mg daily. If indicated, an increase to 60 mg/day total daily dose is often effective. Exceeding a total daily dose of 60 mg rarely increases the beneficial response. OVERDOSAGE Manifestations include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma. Treatment: Essentially symptomatic and supportive. Early gastric lavage is helpful. Keep patient under careful observation and maintain an open airway, since involvement of the extrapyramidal system may produce dysphagia and respiratory difficulty in severe overdosage. If hypotension occurs, the standard measures for managing circulatory shock should be used (I.V. fluids and/or vasoconstrictors). If a vasoconstrictor is needed, levarterenol and phenylephrine are the most suitable drugs. Other pressor agents, including epinephrine, are not recommended, since phenothiazine derivatives may reverse the usual pressor action of these agents and cause further lowering of blood pressure. If CNS depression is marked, symptomatic treatment is indicated. Extrapyramidal symptoms may be treated with antiparkinson drugs. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There are no data on the use of peritoneal or hemodialysis, but they are known to be of little value in phenothiazine intoxication. HOW SUPPLIED Navane (thiothixene) Capsules Bottles of 100’s: 1 mg (NDC 0049-5710-66) 2 mg (NDC 0049-5720-66) 5 mg (NDC 0049-5730-66) 10 mg (NDC 0049-5740-66) 20 mg (NDC 0049-5770-66) Rx only Pfizer Company Logo LAB-0251-7.0 Revised June 2009 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda REFERENCES 1. Worldwide Labeling Safety Report: Dyskinesia and Dyskinesia Tardive and Thiothixene, (16Apr02). 2. Worldwide Labeling Safety Report: Neuroleptic Malignant Syndrome and Thiothixene, (16Apr02). 3. Worldwide Labeling Safety Report: Hyperprolactinemia and Thiothixene, (16Apr02). 4. Ereshefsky L, Saklad SR, Watanabe MD, et al. Thiothixene Pharmacokinetic Interactions: A Study of Hepatic Enzyme Inducers, Clearance Inhibitors, and Demographic Variables. Journal of Clinical Psychopharmacology, 11(5):296–301, (1991). 5. Worldwide Labeling Safety Report: Drug Interaction and Thiothixene, (09May02). 6. McEvoy GK, Miller JL, Snow EK, et al. AHFS Drug Information. American Society of Health-System Pharmacists, Inc., p. 2334-2336, (2002). 7. Worldwide Labeling Safety Report: Menstrual Disorder and Thiothixene, (16Apr02). 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.657306	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016584s059lbl.pdf', 'application_number': 16758, 'submission_type': 'SUPPL ', 'submission_number': 20}
10,919	1 NAVANE® Thiothixene Capsules Thiothixene Hydrochloride Concentrate DESCRIPTION Navane® (thiothixene) is a thioxanthene derivative. Specifically, it is the cis isomer of N,N- dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene] thioxanthene-2-sulfonamide. SO2N(CH3)2 C H CH2CH2N N-CH3 S The thioxanthenes differ from the phenothiazines by the replacement of nitrogen in the central ring with a carbon-linked side chain fixed in space in a rigid structural configuration. An N,N- dimethyl sulfonamide functional group is bonded to the thioxanthene nucleus. Inert ingredients for the capsule formulations are: hard gelatin capsules (which contain gelatin and titanium dioxide; may contain Yellow 10, Yellow 6, Blue 1, Green 3, Red 3, and other inert ingredients); lactose; magnesium stearate; sodium lauryl sulfate; starch. Inert ingredients for the oral concentrate formulation are: alcohol; cherry flavor; dextrose; passion fruit flavor; sorbitol solution; water. ACTIONS Navane is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 INDICATIONS Navane is effective in the management of schizophrenia. Navane has not been evaluated in the management of behavioral complications in patients with mental retardation. CONTRAINDICATIONS Navane is contraindicated in patients with circulatory collapse, comatose states, central nervous system depression due to any cause, and blood dyscrasias. Navane is contraindicated in individuals who have shown hypersensitivity to the drug. It is not known whether there is a cross sensitivity between the thioxanthenes and the phenothiazine derivatives, but this possibility should be considered. WARNINGS Tardive Dyskinesia–Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene(1). Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 (For further information about the description of tardive dyskinesia and its clinical detection, please refer to “Information for Patients” in the PRECAUTIONS section, and to the ADVERSE REACTIONS section.) Neuroleptic Malignant Syndrome (NMS)–A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene(2). Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Usage in Pregnancy–Safe use of Navane during pregnancy has not been established. Therefore, this drug should be given to pregnant patients only when, in the judgment of the physician, the expected benefits from the treatment exceed the possible risks to mother and fetus. Animal reproduction studies and clinical experience to date have not demonstrated any teratogenic effects. In the animal reproduction studies with Navane, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. Similar findings have been reported with other psychotropic agents. After repeated oral administration of Navane to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen. Usage in Children–The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. As is true with many CNS drugs, Navane may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, especially during the first few days of therapy. Therefore, the patient should be cautioned accordingly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 As in the case of other CNS-acting drugs, patients receiving Navane (thiothixene) should be cautioned about the possible additive effects (which may include hypotension) with CNS depressants and with alcohol. PRECAUTIONS An antiemetic effect was observed in animal studies with Navane; since this effect may also occur in man, it is possible that Navane may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor. In consideration of the known capability of Navane and certain other psychotropic drugs to precipitate convulsions, extreme caution should be used in patients with a history of convulsive disorders or those in a state of alcohol withdrawal, since it may lower the convulsive threshold. Although Navane potentiates the actions of the barbiturates, the dosage of the anticonvulsant therapy should not be reduced when Navane is administered concurrently. Though exhibiting rather weak anticholinergic properties, Navane should be used with caution in patients who might be exposed to extreme heat or who are receiving atropine or related drugs. Use with caution in patients with cardiovascular disease. Caution as well as careful adjustment of the dosages is indicated when Navane is used in conjunction with other CNS depressants. Also, careful observation should be made for pigmentary retinopathy and lenticular pigmentation (fine lenticular pigmentation has been noted in a small number of patients treated with Navane for prolonged periods). Blood dyscrasias (agranulocytosis, pancytopenia, thrombocytopenic purpura), and liver damage (jaundice, biliary stasis) have been reported with related drugs. Antipsychotic drugs, including thiothixene(3), elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. Information for Patients: Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. Drug Interactions: Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness.(4,5) Due to a possible additive effect with hypotensive agents, patients receiving these drugs should be observed closely for signs of excessive hypotension when thiothixene is added to their drug regimen.(6) ADVERSE REACTIONS NOTE: Not all of the following adverse reactions have been reported with Navane. However, since Navane has certain chemical and pharmacologic similarities to the phenothiazines, all of the known side effects and toxicity associated with phenothiazine therapy should be borne in mind when Navane is used. Cardiovascular Effects: Tachycardia, hypotension, lightheadedness, and syncope. In the event hypotension occurs, epinephrine should not be used as a pressor agent since a paradoxical further lowering of blood pressure may result. Nonspecific EKG changes have been observed in some patients receiving Navane. These changes are usually reversible and frequently disappear on continued Navane therapy. The incidence of these changes is lower than that observed with some phenothiazines. The clinical significance of these changes is not known. CNS Effects: Drowsiness, usually mild, may occur although it usually subsides with continuation of Navane therapy. The incidence of sedation appears similar to that of the piperazine group of phenothiazines but less than that of certain aliphatic phenothiazines. Restlessness, agitation and insomnia have been noted with Navane. Seizures and paradoxical exacerbation of psychotic symptoms have occurred with Navane infrequently. Hyperreflexia has been reported in infants delivered from mothers having received structurally related drugs. In addition, phenothiazine derivatives have been associated with cerebral edema and cerebrospinal fluid abnormalities. Extrapyramidal Symptoms Extrapyramidal symptoms, such as pseudoparkinsonism, akathisia and dystonia have been reported (see Dystonia, Class effect). Management of these extra-pyramidal symptoms depends upon the type and severity. Rapid relief of acute symptoms may require the use of an injectable antiparkinson agent. More slowly emerging symptoms may be managed by reducing the dosage of Navane and/or administering an oral antiparkinson agent. Dystonia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Persistent Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy with thiothixene(1) or may occur after drug therapy has been discontinued. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities. Since early detection of tardive dyskinesia is important, patients should be monitored on an ongoing basis. It has been reported that fine vermicular movement of the tongue may be an early sign of the syndrome. If this or any other presentation of the syndrome is observed, the clinician should consider possible discontinuation of antipsychotic medication. (See WARNINGS section.) Hepatic Effects: Elevations of serum transaminase and alkaline phosphatase, usually transient, have been infrequently observed in some patients. No clinically confirmed cases of jaundice attributable to Navane (thiothixene) have been reported. Hematologic Effects: As is true with certain other psychotropic drugs, leukopenia and leucocytosis, which are usually transient, can occur occasionally with Navane. Other antipsychotic drugs have been associated with agranulocytosis, eosinophilia, hemolytic anemia, thrombocytopenia and pancytopenia. Allergic Reactions: Rash, pruritus, urticaria, photosensitivity and rare cases of anaphylaxis have been reported with Navane. Undue exposure to sunlight should be avoided. Although not experienced with Navane, exfoliative dermatitis and contact dermatitis (in nursing personnel) have been reported with certain phenothiazines. Endocrine/Reproductive: Hyperprolactinemia(3); lactation, menstrual irregularities, moderate breast enlargement and amenorrhea have occurred in a small percentage of females receiving Navane. If persistent, this may necessitate a reduction in dosage or the discontinuation of therapy. Phenothiazines have been associated with false positive pregnancy tests, gynecomastia, hypoglycemia, hyperglycemia and glycosuria. Autonomic Effects: Dry mouth, blurred vision, nasal congestion, constipation, increased sweating, increased salivation and impotence have occurred infrequently with Navane therapy. Phenothiazines have been associated with miosis, mydriasis, and adynamic ileus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Other Adverse Reactions: Hyperpyrexia, anorexia, nausea, vomiting, diarrhea, increase in appetite and weight, weakness or fatigue, polydipsia, and peripheral edema. Although not reported with Navane, evidence indicates there is a relationship between phenothiazine therapy and the occurrence of a systemic lupus erythematosus-like syndrome. Neuroleptic Malignant Syndrome (NMS): Please refer to the text regarding NMS in the WARNINGS section. NOTE: Sudden deaths have occasionally been reported in patients who have received certain phenothiazine derivatives. In some cases the cause of death was apparently cardiac arrest or asphyxia due to failure of the cough reflex. In others, the cause could not be determined nor could it be established that death was due to phenothiazine administration. DOSAGE AND ADMINISTRATION Dosage of Navane should be individually adjusted depending on the chronicity and severity of the symptoms of schizophrenia. In general, small doses should be used initially and gradually increased to the optimal effective level, based on patient response. Some patients have been successfully maintained on once-a-day Navane therapy. The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. In milder conditions, an initial dose of 2 mg three times daily is recommended. If indicated, a subsequent increase to 15 mg/day total daily dose is often effective. In more severe conditions, an initial dose of 5 mg twice daily is recommended. The usual optimal dose is 20 to 30 mg daily. If indicated, an increase to 60 mg/day total daily dose is often effective. Exceeding a total daily dose of 60 mg rarely increases the beneficial response. OVERDOSAGE Manifestations include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma. Treatment: Essentially symptomatic and supportive. Early gastric lavage is helpful. Keep patient under careful observation and maintain an open airway, since involvement of the extrapyramidal system may produce dysphagia and respiratory difficulty in severe overdosage. If hypotension occurs, the standard measures for managing circulatory shock should be used (I.V. fluids and/or vasoconstrictors). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 If a vasoconstrictor is needed, levarterenol and phenylephrine are the most suitable drugs. Other pressor agents, including epinephrine, are not recommended, since phenothiazine derivatives may reverse the usual pressor action of these agents and cause further lowering of blood pressure. If CNS depression is marked, symptomatic treatment is indicated. Extrapyramidal symptoms may be treated with antiparkinson drugs. There are no data on the use of peritoneal or hemodialysis, but they are known to be of little value in phenothiazine intoxication. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 HOW SUPPLIED Navane (thiothixene) Capsules Bottles of 100’s: 1 mg (NDC 0049-5710-66) 2 mg (NDC 0049-5720-66) 5 mg (NDC 0049-5730-66) 10 mg (NDC 0049-5740-66) 20 mg (NDC 0049-5770-66) Rx only LAB-0251-4.0 Revised January 2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 REFERENCES 1. Worldwide Labeling Safety Report: Dyskinesia and Dyskinesia Tardive and Thiothixene, (16Apr02). 2. Worldwide Labeling Safety Report: Neuroleptic Malignant Syndrome and Thiothixene, (16Apr02). 3. Worldwide Labeling Safety Report: Hyperprolactinemia and Thiothixene, (16Apr02). 4. Ereshefsky L, Saklad SR, Watanabe MD, et al. Thiothixene Pharmacokinetic Interactions: A Study of Hepatic Enzyme Inducers, Clearance Inhibitors, and Demographic Variables. Journal of Clinical Psychopharmacology, 11(5):296–301, (1991). 5. Worldwide Labeling Safety Report: Drug Interaction and Thiothixene, (09May02). 6. McEvoy GK, Miller JL, Snow EK, et al. AHFS Drug Information. American Society of Health-System Pharmacists, Inc., p. 2334-2336, (2002). 7. Worldwide Labeling Safety Report: Menstrual Disorder and Thiothixene, (16Apr02). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.689506	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/016584057,016758s019,016904s033lbl.pdf', 'application_number': 16758, 'submission_type': 'SUPPL ', 'submission_number': 19}
10,923	Pliva Surmontil Rev. 6/07 Size: 13 x 16.5 Fold: 1-3/8 x 1-3/8 Type: 6 pt. Page 1 6/22/07 JB DESCRIPTION Surmontil (trimipramine maleate) is 5-(3-dimethylamino-2-methylpropyl)-10,11- dihydro-5H-dibenz (b,f) azepine acid maleate (racemic form). Molecular Formula: C20H26N2 • C4H4O4 Molecular Weight: 410.5 Surmontil capsules contain trimipramine maleate equivalent to 25 mg, 50 mg, or 100 mg of trimipramine as the base. The inactive ingredients present are black ink, FD&C Blue 1, gelatin, lactose, magnesium stearate, and titanium dioxide. The 25 mg dosage strength also contains benzyl alcohol, D&C Yellow 10, edetate calcium disodium, FD&C Yellow 6, parabens (butyl, propyl and methyl), sodium lauryl sulfate, and sodium propionate; the 50 mg dosage strength also contains benzyl alcohol, D&C Red 28, edetate calcium disodium, FD&C Red 40, FD&C Yellow 6, parabens (butyl, propyl and methyl), sodium lauryl sulfate, and sodium propionate. Trimipramine maleate is prepared as a racemic mixture which can be resolved into levorotatory and dextrorotatory isomers. The asymmetric center responsible for optical isomerism is marked in the formula by an asterisk. Trimipramine maleate is an almost odorless, white or slightly cream-colored, crystalline substance, melting at 140°-144° C. It is very slightly soluble in ether and water, is slightly soluble in ethyl alcohol and acetone, and freely soluble in chloroform and methanol at 20° C. CLINICAL PHARMACOLOGY Surmontil is an antidepressant with an anxiety-reducing sedative component to its action. The mode of action of Surmontil on the central nervous system is not known. However, unlike amphetamine-type compounds it does not act primarily by stimulation of the central nervous system. It does not act by inhibition of the monoamine oxidase system. The single-dose pharmacokinetics of trimipramine were evaluated in a comparative study of 24 elderly subjects and 24 younger subjects; no clinically relevant differences were demonstrated based on age or gender. INDICATIONS AND USAGE Surmontil is indicated for the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. In studies with neurotic out- patients, the drug appeared to be equivalent to amitriptyline in the less-depressed patients but somewhat less effective than amitriptyline in the more severely depressed patients. In hospitalized depressed patients, trimipramine and imipramine were equally effective in relieving depression. CONTRAINDICATIONS Surmontil is contraindicated in cases of known hypersensitivity to the drug. The possibility of cross-sensitivity to other dibenzazepine compounds should be kept in mind. Surmontil should not be given in conjunction with drugs of the monoamine oxidase inhibitor class (e.g., tranylcypromine, isocarboxazid or phenelzine sulfate). The concomitant use of monoamine oxidase inhibitors (MAOI) and tricyclic compounds similar to Surmontil has caused severe hyperpyretic reactions, convulsive crises, and death in some patients. At least two weeks should elapse after cessation of therapy with MAOI before instituting therapy with Surmontil. Initial dosage should be low and increased gradually with caution and careful observation of the patient. The drug is contraindicated during the acute recovery period after a myocardial infarction. WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (aged 18-24) with major depres- sive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analysis of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders including a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable with age strada and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases N CH2 CH2 CH (CH ) 3 3 2 N (CH ) * • C H O 4 4 4 Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Surmontil or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant ther- apy should be monitored appropriately and observed closely for clinical worsening, suici- dality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Surmontil is not approved for use in pediatric patients. (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use) B08-0718 SURMONTIL® (Trimipramine Maleate) Rx only Rev. 6/07 depressive disorder or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and care- givers. Prescriptions for Surmontil should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depression symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Surmontil is not approved for use in treating bipolar depression. General Consideration for Use Extreme caution should be used when this drug is given to patients with any evidence of cardiovascular disease because of the possibility of conduction defects, arrhythmias, myocardial infarction, strokes, and tachycardia. Caution is advised in patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold; patients receiving guanethidine or similar agents, since Surmontil (trimipramine maleate) may block the pharmacologic effects of these drugs. Since the drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly. PRECAUTIONS General The possibility of suicide is inherent in any severely depressed patient and persists until a significant remission occurs. When a patient with a serious suicidal potential is not hospitalized, the prescription should be for the smallest amount feasible. In schizophrenic patients activation of the psychosis may occur and require reduction of dosage or the addition of a major tranquilizer to the therapeutic regime. Manic or hypomanic episodes may occur in some patients, in particular those with cyclic-type disorders. In some cases therapy with Surmontil must be discontinued until the episode is relieved, after which therapy may be reinstituted at lower dosages if still required. Concurrent administration of Surmontil and electroshock therapy may increase the hazards of therapy. Such treatment should be limited to those patients for whom it is essential. When possible, discontinue the drug for several days prior to elective surgery. Surmontil should be used with caution in patients with impaired liver function. Chronic animal studies showed occasional occurrence of hepatic congestion, fatty infiltration, or increased serum liver enzymes at the highest dose of 60 mg/kg/day. Both elevation and lowering of blood sugar have been reported with tricyclic antidepressants. Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Surmontil and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Surmontil. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Surmontil. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Drug Interactions Cimetidine There is evidence that cimetidine inhibits the elimination of tricyclic antidepressants. Downward adjustment of Surmontil dosage may be required if cimetidine therapy is initiated; upward adjustment if cimetidine therapy is discontinued. Alcohol Patients should be warned that the concomitant use of alcoholic beverages may be associated with exaggerated effects. Catecholamines/Anticholinergics It has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Similarly, atropinelike effects may be more pronounced in patients receiving anticholinergic therapy. Therefore, particular care should be exercised when it is necessary to administer tricyclic antidepressants with sympathomimetic amines, local decongestants, local anesthetics containing epinephrine, atropine or drugs with an anticholinergic effect. In resistant cases of depression in adults, a dose of 2.5 mg/kg/day may have to be exceeded. If a higher dose is needed, ECG monitoring should be maintained during the initiation of therapy and at appropriate intervals during stabilization of dose. Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7- 10% of caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of the isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Carcinogenesis, Mutagenesis, Impairment of Fertility Semen studies in man (four schizophrenics and nine normal volunteers) revealed no significant changes in sperm morphology. It is recognized that drugs having a parasympathetic effect, including tricyclic antidepressants, may alter the ejaculatory response. Chronic animal studies showed occasional evidence of degeneration of seminiferous tubules at the highest dose of 60 mg/kg/day. Pregnancy Teratogenic Effects—Pregnancy Category C Surmontil has shown evidence of embryotoxicity and/or increased incidence of major Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medi- cines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treat- ment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depres- sion and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an anti- depressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medi- cines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treat- ment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depres- sion and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an anti- depressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medi- cines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treat- ment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depres- sion and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an anti- depressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/ hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. Poisindex® Toxicologic Management. Topic: Antidepressants, Tricyclic Micromedex Inc. Vol. 85. HOW SUPPLIED Surmontil® (trimipramine maleate) Capsules 25 mg — Opaque blue and yellow capsule in bottles of 100. Printed OP and 718 50 mg — Opaque blue and orange capsule in bottles of 100. Printed OP and 719. 100 mg —Opaque blue and white capsule in bottles of 100. Printed OP and 720 Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature]. Keep bottles tightly closed. Dispense in a tight container. Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the health- care provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • new or worse irritability • attempts to commit suicide • acting aggressive, being angry, or violent • new or worse depression • acting on dangerous impulses • new or worse anxiety • an extreme increase in activity and talking • feeling very agitated or restless (mania) • panic attacks • other unusual changes in behavior or mood • trouble sleeping (insomnia) What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the health- care provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. DURAMED PHARMACEUTICALS, INC. Subsidiary of Barr Pharmaceuticals, Inc. Pomona, New York 10970 Revised JUNE 2007 Br-718, 719, 720 B08-0718 c/n.1 • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. DURAMED PHARMACEUTICALS, INC. Subsidiary of Barr Pharmaceuticals, Inc. Pomona, New York 10970 B08-0718 Rev. 6/07 • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. DURAMED PHARMACEUTICALS, INC. Subsidiary of Barr Pharmaceuticals, Inc. Pomona, New York 10970 B08-0718 Rev. 6/07 • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. DURAMED PHARMACEUTICALS, INC. Subsidiary of Barr Pharmaceuticals, Inc. Pomona, New York 10970 B08-0718 Rev. 6/07 Pliva Surmontil Rev. 6/07 Size: 13 x 16.5 Fold: 1-3/8 x 1-3/8 Type: 6 pt. Page 2 6/22/07 JB anomalies in rats or rabbits at doses 20 times the human dose. There are no adequate and well-controlled studies in pregnant women. Surmontil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS–Clinical Worsening and Suicide Risk). Anyone considering the use of Surmontil in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use Clinical studies of Surmontil® (trimipramine maleate) were not adequate to determine whether subjects aged 65 and over respond differently from younger subjects. The pharmacokinetics of trimipramine were not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). Surmontil is known to be substantially excreted by the kidney. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered (see PRECAUTIONS — General). Greater sensitivity (e.g., confusional states, sedation) of some older individuals cannot be ruled out (see ADVERSE REACTIONS). In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Note: The pharmacological similarities among the tricyclic antidepressants require that each of the reactions be considered when Surmontil is administered. Some of the adverse reactions included in this listing have not in fact been reported with Surmontil. Cardiovascular Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke. Psychiatric Confusional states (especially the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis. Neurological Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus; syndrome of inappropriate ADH (antidiuretic hormone) secretion. Anticholinergic Dry mouth and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis, constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. Allergic Skin rash, petechiae, urticaria, itching, photosensitization, edema of face and tongue. Hematologic Bone-marrow depression including agranulocytosis, eosinophilia; purpura; thrombo- cytopenia. Leukocyte and differential counts should be performed in any patient who develops fever and sore throat during therapy; the drug should be discontinued if there is evidence of pathological neutrophil depression. Gastrointestinal Nausea and vomiting, anorexia, epigastric distress, diarrhea, peculiar taste, stomatitis, abdominal cramps, black tongue. Endocrine Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood- sugar levels. Other Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness, and fatigue; headache; parotid swelling; alopecia. Withdrawal Symptoms Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise. DOSAGE AND ADMINISTRATION Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance. Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision. It is not possible to prescribe a single dosage schedule of Surmontil that will be therapeutically effective in all patients. The physical psychodynamic factors contributing to depressive symptomatology are very complex; spontaneous remissions or exacerbations of depressive symptoms may occur with or without drug therapy. Consequently, the recommended dosage regimens are furnished as a guide which may be modified by factors such as the age of the patient, chronicity and severity of the disease, medical condition of the patient, and degree of psychotherapeutic support. Most antidepressant drugs have a lag period of ten days to four weeks before a therapeutic response is noted. Increasing the dose will not shorten this period but rather increase the incidence of adverse reactions. Usual Adult Dose Outpatients and Office Patients —Initially, 75 mg/day in divided doses, increased to 150 mg/day. Dosages over 200 mg/day are not recommended. Maintenance therapy is in the range of 50 to 150 mg/day. For convenient therapy and to facilitate patient compliance, the total dosage requirement may be given at bedtime. Hospitalized Patients—Initially, 100 mg/day in divided doses. This may be increased gradually in a few days to 200 mg/day, depending upon individual response and tolerance. If improvement does not occur in 2 to 3 weeks, the dose may be increased to the maximum recommended dose of 250 to 300 mg/day. Adolescent and Geriatric Patients—Initially, a dose of 50 mg/day is recommended, with gradual increments up to 100 mg/day, depending upon patient response and tolerance. Maintenance—Following remission, maintenance medication may be required for a longer period of time, at the lowest dose that will maintain remission. Maintenance therapy is preferably administered as a single dose at bedtime. To minimize relapse, maintenance therapy should be continued for about three months. OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital monitoring is required as soon as possible. Manifestations Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic anti- depressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Management General Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Plasma drug levels may not reflect the severity of the poisoning. Therefore, monitoring of plasma drug levels alone should not guide management of the patient. Gastrointestinal Decontamination All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular A maximal limb-lead QRS duration of ≥0.10 seconds has been associated with an increased incidence of seizures. A QRS duration of ≥0.16 seconds has been associated with an increased incidence of ventricular dysrhythmias. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation SURMONTIL® (Trimipramine Maleate) 080718 (Three Medication Guides Attached) Revised JUNE 2007 11001244 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.912752	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016792s025lbl.pdf', 'application_number': 16792, 'submission_type': 'SUPPL ', 'submission_number': 25}
10,922	Attachment 1 Page 1 Class Suicidality Labeling Language for Antidepressants [This section should be located at the beginning of the package insert with bolded font and enclosed in a black box] [Insert established name] Suicidality in Children and Adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Insert established name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. [Insert established name] is not approved for use in pediatric patients. (See Warnings and Precautions: Pediatric Use) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. [This section should be located under WARNINGS. Please note that the title of this section should be bolded, and it should be the first paragraph in this section.] WARNINGS-Clinical Worsening and Suicide Risk Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. A causal role for antidepressants in inducing suicidality has been established in pediatric patients. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 1 Page 2 There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for [Insert established name] should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 1 Page 3 above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established name] is not approved for use in treating bipolar depression. [This section should be located under PRECAUTIONS, Information for Patients.] Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with [Insert established name] and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Adolescents is available for [Insert established name]. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking [Insert established name]. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. [This section should be located under PRECAUTIONS, Pediatric Use.] Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of [Insert established name] in a child or adolescent must balance the potential risks with the clinical need. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 1 Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions 2. How to try to prevent suicidal thoughts or actions in your child 3. You should watch for certain signs if your child is taking an antidepressant 4. There are benefits and risks when using antidepressants 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. Whenever an antidepressant is started or its dose is changed, pay close attention to your child. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 2 After starting an antidepressant, your child should generally see his or her healthcare provider: • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your healthcare provider's advice about how often to come back • More often if problems or questions arise (see other side) You should call your child's healthcare provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child's healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms. 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) . This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 3 Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:03.973067	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/16792s024lbl.pdf', 'application_number': 16792, 'submission_type': 'SUPPL ', 'submission_number': 24}
10,925	SURMONTIL® (Trimipramine Maleate) Rx only Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of SURMONTIL or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SURMONTIL is not approved for use in pediatric patients. (See WARNINGS - Clinical Worsening and Suicide Risk, PRECAUTIONS - Information for Patients, and PRECAUTIONS Pediatric Use) DESCRIPTION SURMONTIL (trimipramine maleate) is 5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz (b,f) azepine acid maleate (racemic form). structural formula Molecular Formula: C20H26N2 • C4H4O4 Molecular Weight: 410.5 SURMONTIL capsules contain trimipramine maleate equivalent to 25 mg, 50 mg, or 100 mg of trimipramine as the base. The inactive ingredients present are black ink, FD&C Blue 1, gelatin, lactose, magnesium stearate, and titanium dioxide. The 25 mg dosage strength also contains benzyl alcohol, D&C Yellow 10, edetate calcium disodium, FD&C Yellow 6, parabens (butyl, propyl and methyl), sodium lauryl sulfate, and sodium propionate; the 50 mg dosage strength also contains benzyl alcohol, D&C Red 28, edetate calcium disodium, FD&C Red 40, FD&C Yellow 6, parabens (butyl, propyl and methyl), sodium lauryl sulfate, and sodium propionate. Trimipramine maleate is prepared as a racemic mixture which can be resolved into levorotatory and dextrorotatory isomers. The asymmetric center responsible for optical isomerism is marked in the formula by an asterisk. Trimipramine maleate is an almost odorless, white or slightly cream-colored, crystalline substance, melting at 140°-144° C. It is very slightly soluble in ether and water, is slightly soluble in ethyl alcohol and acetone, and freely soluble in chloroform and methanol at 20° C. 1 Reference ID: 3594266 CLINICAL PHARMACOLOGY SURMONTIL is an antidepressant with an anxiety-reducing sedative component to its action. The mode of action of SURMONTIL on the central nervous system is not known. However, unlike amphetamine-type compounds it does not act primarily by stimulation of the central nervous system. It does not act by inhibition of the monoamine oxidase system. The single-dose pharmacokinetics of trimipramine were evaluated in a comparative study of 24 elderly subjects and 24 younger subjects; no clinically relevant differences were demonstrated based on age or gender. INDICATIONS AND USAGE SURMONTIL is indicated for the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. In studies with neurotic outpatients, the drug appeared to be equivalent to amitriptyline in the less-depressed patients but somewhat less effective than amitriptyline in the more severely depressed patients. In hospitalized depressed patients, trimipramine and imipramine were equally effective in relieving depression. CONTRAINDICATIONS Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with SURMONTIL or within 14 days of stopping treatment with SURMONTIL is contraindicated because of an increased risk of serotonin syndrome. The use of SURMONTIL within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). Starting SURMONTIL in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION). Hypersensitivity to Tricyclic Antidepressants Cross-sensitivity between SURMONTIL and other dibenzazepines is a possibility. Myocardial Infarction The drug is contraindicated during the acute recovery period after a myocardial infarction. WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (aged 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. 2 Reference ID: 3594266 The pooled analysis of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders including a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable with age strada and across indications. These risk differences (drug placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for SURMONTIL should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. 3 Reference ID: 3594266 However, prior to initiating treatment with an antidepressant, patients with depression symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that SURMONTIL is not approved for use in treating bipolar depression. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including SURMONTIL, alone, but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of SURMONTIL with MAOIs intended to treat psychiatric disorders is contraindicated. SURMONTIL should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking SURMONTIL. SURMONTIL should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of SURMONTIL with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with SURMONTIL and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including SURMONTIL may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. General Consideration for Use Extreme caution should be used when this drug is given to patients with any evidence of cardiovascular disease because of the possibility of conduction defects, arrhythmias, myocardial infarction, strokes, and tachycardia. Caution is advised in patients with history of urinary retention because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold; patients receiving guanethidine or similar agents, since SURMONTIL (trimipramine maleate) may block the pharmacologic effects of these drugs. 4 Reference ID: 3594266 Since the drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly. PRECAUTIONS General The possibility of suicide is inherent in any severely depressed patient and persists until a significant remission occurs. When a patient with a serious suicidal potential is not hospitalized, the prescription should be for the smallest amount feasible. In schizophrenic patients activation of the psychosis may occur and require reduction of dosage or the addition of a major tranquilizer to the therapeutic regimen. Manic or hypomanic episodes may occur in some patients, in particular those with cyclic-type disorders. In some cases therapy with SURMONTIL must be discontinued until the episode is relieved, after which therapy may be reinstituted at lower dosages if still required. Concurrent administration of SURMONTIL and electroshock therapy may increase the hazards of therapy. Such treatment should be limited to those patients for whom it is essential. When possible, discontinue the drug for several days prior to elective surgery. SURMONTIL should be used with caution in patients with impaired liver function. Chronic animal studies showed occasional occurrence of hepatic congestion, fatty infiltration, or increased serum liver enzymes at the highest dose of 60 mg/kg/day. Both elevation and lowering of blood sugar have been reported with tricyclic antidepressants. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with SURMONTIL and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for SURMONTIL. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking SURMONTIL. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be advised that taking SURMONTIL can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open- angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. 5 Reference ID: 3594266 Drug Interactions Cimetidine There is evidence that cimetidine inhibits the elimination of tricyclic antidepressants. Downward adjustment of SURMONTIL dosage may be required if cimetidine therapy is initiated; upward adjustment if cimetidine therapy is discontinued. Alcohol Patients should be warned that the concomitant use of alcoholic beverages may be associated with exaggerated effects. Catecholamines/Anticholinergics It has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Similarly, atropine-like effects may be more pronounced in patients receiving anticholinergic therapy. Therefore, particular care should be exercised when it is necessary to administer tricyclic antidepressants with sympathomimetic amines, local decongestants, local anesthetics containing epinephrine, atropine or drugs with an anticholinergic effect. In resistant cases of depression in adults, a dose of 2.5 mg/kg/day may have to be exceeded. If a higher dose is needed, ECG monitoring should be maintained during the initiation of therapy and at appropriate intervals during stabilization of dose. Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10% of caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of the isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Monoamine Oxidase Inhibitors (MAOIs) (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Serotonergic Drugs (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) 6 Reference ID: 3594266 Carcinogenesis, Mutagenesis, Impairment of Fertility Semen studies in man (four schizophrenics and nine normal volunteers) revealed no significant changes in sperm morphology. It is recognized that drugs having a parasympathetic effect, including tricyclic antidepressants, may alter the ejaculatory response. Chronic animal studies showed occasional evidence of degeneration of seminiferous tubules at the highest dose of 60 mg/kg/day. Pregnancy Teratogenic Effects Pregnancy Category C SURMONTIL has shown evidence of embryotoxicity and/or increased incidence of major anomalies in rats or rabbits at doses 20 times the human dose. There are no adequate and well-controlled studies in pregnant women. SURMONTIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS - Clinical Worsening and Suicide Risk). Anyone considering the use of SURMONTIL in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use Clinical studies of SURMONTIL (trimipramine maleate) were not adequate to determine whether subjects aged 65 and over respond differently from younger subjects. The pharmacokinetics of trimipramine were not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). SURMONTIL is known to be substantially excreted by the kidney. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered (see PRECAUTIONS - General). Greater sensitivity (e.g., confusional states, sedation) of some older individuals cannot be ruled out (see ADVERSE REACTIONS). In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Note: The pharmacological similarities among the tricyclic antidepressants require that each of the reactions be considered when SURMONTIL is administered. Some of the adverse reactions included in this listing have not in fact been reported with SURMONTIL. Cardiovascular Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke. Psychiatric Confusional states (especially the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis. 7 Reference ID: 3594266 Neurological Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus; syndrome of inappropriate ADH (antidiuretic hormone) secretion. Anticholinergic Dry mouth and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis, constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. Allergic Skin rash, petechiae, urticaria, itching, photosensitization, edema of face and tongue. Hematologic Bone marrow depression including agranulocytosis, eosinophilia; purpura; thrombocytopenia. Leukocyte and differential counts should be performed in any patient who develops fever and sore throat during therapy; the drug should be discontinued if there is evidence of pathological neutrophil depression. Gastrointestinal Nausea and vomiting, anorexia, epigastric distress, diarrhea, peculiar taste, stomatitis, abdominal cramps, black tongue. Endocrine Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels. Other Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness, and fatigue; headache; parotid swelling; alopecia. Withdrawal Symptoms Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise. DOSAGE AND ADMINISTRATION Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance. Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision. It is not possible to prescribe a single dosage schedule of SURMONTIL that will be therapeutically effective in all patients. The physical psychodynamic factors contributing to depressive symptomatology are very complex; spontaneous remissions or exacerbations of depressive symptoms may occur with or without drug therapy. Consequently, the recommended dosage regimens are furnished as a guide which may be modified by factors such as the age of 8 Reference ID: 3594266 the patient, chronicity and severity of the disease, medical condition of the patient, and degree of psychotherapeutic support. Most antidepressant drugs have a lag period of ten days to four weeks before a therapeutic response is noted. Increasing the dose will not shorten this period but rather increase the incidence of adverse reactions. Usual Adult Dose Outpatients and Office Patients —Initially, 75 mg/day in divided doses, increased to 150 mg/day. Dosages over 200 mg/day are not recommended. Maintenance therapy is in the range of 50 to 150 mg/day. For convenient therapy and to facilitate patient compliance, the total dosage requirement may be given at bedtime. Hospitalized Patients—Initially, 100 mg/day in divided doses. This may be increased gradually in a few days to 200 mg/day, depending upon individual response and tolerance. If improvement does not occur in 2 to 3 weeks, the dose may be increased to the maximum recommended dose of 250 to 300 mg/day. Adolescent and Geriatric Patients—Initially, a dose of 50 mg/day is recommended, with gradual increments up to 100 mg/day, depending upon patient response and tolerance. Maintenance—Following remission, maintenance medication may be required for a longer period of time, at the lowest dose that will maintain remission. Maintenance therapy is preferably administered as a single dose at bedtime. To minimize relapse, maintenance therapy should be continued for about three months. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with SURMONTIL. Conversely, at least 14 days should be allowed after stopping SURMONTIL before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of SURMONTIL With Other MAOIs, Such as Linezolid or Methylene Blue: Do not start SURMONTIL in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). In some cases, a patient already receiving therapy with SURMONTIL may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, SURMONTIL should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with SURMONTIL may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with SURMONTIL is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). OVERDOSAGE* Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital monitoring is required as soon as possible. 9 Reference ID: 3594266 Manifestations Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Management General Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Plasma drug levels may not reflect the severity of the poisoning. Therefore, monitoring of plasma drug levels alone should not guide management of the patient. Gastrointestinal Decontamination All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular A maximal limb-lead QRS duration of ≥ 0.10 seconds has been associated with an increased incidence of seizures. A QRS duration of ≥ 0.16 seconds has been associated with an increased incidence of ventricular dysrhythmias. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. 10 Reference ID: 3594266 Pediatric Management The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. *Poisindex® Toxicologic Management. Topic: Antidepressants, Tricyclic Micromedex Inc. Vol. 85. HOW SUPPLIED SURMONTIL (trimipramine maleate) Capsules 25 mg — Opaque blue and yellow capsule in bottles of 100 (NDC 51285-538-02). Printed OP and 718 50 mg — Opaque blue and orange capsule in bottles of 100 (NDC 51285-539-02). Printed OP and 719 100 mg — Opaque blue and white capsule in bottles of 100 (NDC 51285-554-02). Printed OP and 720 Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature]. Keep bottles tightly closed. Dispense in a tight container. Teva Select Brands, Horsham, PA 19044, Division of Teva Pharmaceuticals USA, Inc. SUR-002 Iss. 05/2014 11 Reference ID: 3594266 Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? o Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. o Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. o Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood Visual Problems • eye pain 12 Reference ID: 3594266 • changes in vision • swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Who should not take SURMONTIL? • Do not take SURMONTIL if you take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. • Do not take an MAOI within 2 weeks of stopping SURMONTIL unless directed to do so by your physician. • Do not start SURMONTIL if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised May 2014 Teva Select Brands, Horsham, PA 19044, Division of Teva Pharmaceuticals USA, Inc. SURMG-002 Iss. 05/2014 13 Reference ID: 3594266	custom-source	2025-02-12T13:44:04.131307	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016792s037lbl.pdf', 'application_number': 16792, 'submission_type': 'SUPPL ', 'submission_number': 37}
10,927	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.199866	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/16851s51lbl.pdf', 'application_number': 16851, 'submission_type': 'SUPPL ', 'submission_number': 51}
10,926	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.250959	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/016831s049lbl.pdf', 'application_number': 16831, 'submission_type': 'SUPPL ', 'submission_number': 49}
10,924	SURMONTIL® (Trimipramine Maleate) Rx only Rev. November 2012 XXXXX Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Surmontil or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Surmontil is not approved for use in pediatric patients. (See WARNINGS - Clinical Worsening and Suicide Risk,PRECAUTIONS - Information for Patients, and PRECAUTIONS - Pediatric Use) DESCRIPTION Surmontil (trimipramine maleate) is 5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H dibenz (b,f) azepine acid maleate (racemic form). structure Molecular Formula: C20H26N2 • C4H4O4 Molecular Weight: 410.5 1 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Surmontil capsules contain trimipramine maleate equivalent to 25 mg, 50 mg, or 100 mg of trimipramine as the base. The inactive ingredients present are black ink, FD&C Blue 1, gelatin, lactose, magnesium stearate, and titanium dioxide. The 25 mg dosage strength also contains benzyl alcohol, D&C Yellow 10, edetate calcium disodium, FD&C Yellow 6, parabens (butyl, propyl and methyl), sodium lauryl sulfate, and sodium propionate; the 50 mg dosage strength also contains benzyl alcohol, D&C Red 28, edetate calcium disodium, FD&C Red 40, FD&C Yellow 6, parabens (butyl, propyl and methyl), sodium lauryl sulfate, and sodium propionate. Trimipramine maleate is prepared as a racemic mixture which can be resolved into levorotatory and dextrorotatory isomers. The asymmetric center responsible for optical isomerism is marked in the formula by an asterisk. Trimipramine maleate is an almost odorless, white or slightly cream-colored, crystalline substance, melting at 140°-144° C. It is very slightly soluble in ether and water, is slightly soluble in ethyl alcohol and acetone, and freely soluble in chloroform and methanol at 20° C. CLINICAL PHARMACOLOGY Surmontil is an antidepressant with an anxiety-reducing sedative component to its action. The mode of action of Surmontil on the central nervous system is not known. However, unlike amphetamine-type compounds it does not act primarily by stimulation of the central nervous system. It does not act by inhibition of the monoamine oxidase system. The single-dose pharmacokinetics of trimipramine were evaluated in a comparative study of 24 elderly subjects and 24 younger subjects; no clinically relevant differences were demonstrated based on age or gender. INDICATIONS AND USAGE Surmontil is indicated for the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. In studies with neurotic outpatients, the drug appeared to be equivalent to amitriptyline in the less-depressed patients but somewhat less effective than amitriptyline in the more severely depressed patients. In hospitalized depressed patients, trimipramine and imipramine were equally effective in relieving depression. CONTRAINDICATIONS Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with Surmontil or within 14 days of stopping treatment with Surmontil is contraindicated because of an increased risk of serotonin syndrome. The use of Surmontil within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). Starting Surmontil in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION). 2 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypersensitivity to Tricyclic Antidepressants Cross-sensitivity between Surmontil and other dibenzazepines is a possibility. Myocardial Infarction The drug is contraindicated during the acute recovery period after a myocardial infarction. WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (aged 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analysis of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders including a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable with age strada and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥ 65 6 fewer cases 3 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Surmontil should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depression symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Surmontil is not approved for use in treating bipolar depression. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Surmontil, alone, but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s wort) and with drugs that impair metabolism of serotonin 4 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of Surmontil with MAOIs intended to treat psychiatric disorders is contraindicated. Surmontil should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Surmontil. Surmontil should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of Surmontil with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Surmontil and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. General Consideration for Use Extreme caution should be used when this drug is given to patients with any evidence of cardiovascular disease because of the possibility of conduction defects, arrhythmias, myocardial infarction, strokes, and tachycardia. Caution is advised in patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold; patients receiving guanethidine or similar agents, since Surmontil (trimipramine maleate) may block the pharmacologic effects of these drugs. Since the drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly. 5 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General The possibility of suicide is inherent in any severely depressed patient and persists until a significant remission occurs. When a patient with a serious suicidal potential is not hospitalized, the prescription should be for the smallest amount feasible. In schizophrenic patients activation of the psychosis may occur and require reduction of dosage or the addition of a major tranquilizer to the therapeutic regime. Manic or hypomanic episodes may occur in some patients, in particular those with cyclic-type disorders. In some cases therapy with Surmontil must be discontinued until the episode is relieved, after which therapy may be reinstituted at lower dosages if still required. Concurrent administration of Surmontil and electroshock therapy may increase the hazards of therapy. Such treatment should be limited to those patients for whom it is essential. When possible, discontinue the drug for several days prior to elective surgery. Surmontil should be used with caution in patients with impaired liver function. Chronic animal studies showed occasional occurrence of hepatic congestion, fatty infiltration, or increased serum liver enzymes at the highest dose of 60 mg/kg/day. Both elevation and lowering of blood sugar have been reported with tricyclic antidepressants. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Surmontil and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Surmontil. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Surmontil. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. 6 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Cimetidine There is evidence that cimetidine inhibits the elimination of tricyclic antidepressants. Downward adjustment of Surmontil dosage may be required if cimetidine therapy is initiated; upward adjustment if cimetidine therapy is discontinued. Alcohol Patients should be warned that the concomitant use of alcoholic beverages may be associated with exaggerated effects. Catecholamines/Anticholinergics It has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Similarly, atropine-like effects may be more pronounced in patients receiving anticholinergic therapy. Therefore, particular care should be exercised when it is necessary to administer tricyclic antidepressants with sympathomimetic amines, local decongestants, local anesthetics containing epinephrine, atropine or drugs with an anticholinergic effect. In resistant cases of depression in adults, a dose of 2.5 mg/kg/day may have to be exceeded. If a higher dose is needed, ECG monitoring should be maintained during the initiation of therapy and at appropriate intervals during stabilization of dose. Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10% of caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of the isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). 7 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Monoamine Oxidase Inhibitors (MAOIs) (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Serotonergic Drugs (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Carcinogenesis, Mutagenesis, Impairment of Fertility Semen studies in man (four schizophrenics and nine normal volunteers) revealed no significant changes in sperm morphology. It is recognized that drugs having a parasympathetic effect, including tricyclic antidepressants, may alter the ejaculatory response. Chronic animal studies showed occasional evidence of degeneration of seminiferous tubules at the highest dose of 60 mg/kg/day. Pregnancy Teratogenic Effects Pregnancy Category C Surmontil has shown evidence of embryotoxicity and/or increased incidence of major anomalies in rats or rabbits at doses 20 times the human dose. There are no adequate and well-controlled studies in pregnant women. Surmontil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS–Clinical Worsening and Suicide Risk). Anyone considering the use of Surmontil in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use Clinical studies of Surmontil® (trimipramine maleate) were not adequate to determine whether subjects aged 65 and over respond differently from younger subjects. The pharmacokinetics of trimipramine were not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). Surmontil is known to be substantially excreted by the kidney. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered (see PRECAUTIONS - General). 8 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Greater sensitivity (e.g., confusional states, sedation) of some older individuals cannot be ruled out (see ADVERSE REACTIONS). In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Note: The pharmacological similarities among the tricyclic antidepressants require that each of the reactions be considered when Surmontil is administered. Some of the adverse reactions included in this listing have not in fact been reported with Surmontil. Cardiovascular Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke. Psychiatric Confusional states (especially the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis. Neurological Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus; syndrome of inappropriate ADH (antidiuretic hormone) secretion. Anticholinergic Dry mouth and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis, constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. Allergic Skin rash, petechiae, urticaria, itching, photosensitization, edema of face and tongue. Hematologic Bone-marrow depression including agranulocytosis, eosinophilia; purpura; thrombocytopenia. Leukocyte and differential counts should be performed in any patient who develops fever and sore throat during therapy; the drug should be discontinued if there is evidence of pathological neutrophil depression. Gastrointestinal Nausea and vomiting, anorexia, epigastric distress, diarrhea, peculiar taste, stomatitis, abdominal cramps, black tongue. 9 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Endocrine Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood-sugar levels. Other Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness, and fatigue; headache; parotid swelling; alopecia. Withdrawal Symptoms Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise. DOSAGE AND ADMINISTRATION Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance. Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision. It is not possible to prescribe a single dosage schedule of Surmontil that will be therapeutically effective in all patients. The physical psychodynamic factors contributing to depressive symptomatology are very complex; spontaneous remissions or exacerbations of depressive symptoms may occur with or without drug therapy. Consequently, the recommended dosage regimens are furnished as a guide which may be modified by factors such as the age of the patient, chronicity and severity of the disease, medical condition of the patient, and degree of psychotherapeutic support. Most antidepressant drugs have a lag period of ten days to four weeks before a therapeutic response is noted. Increasing the dose will not shorten this period but rather increase the incidence of adverse reactions. Usual Adult Dose Outpatients and Office Patients —Initially, 75 mg/day in divided doses, increased to 150 mg/day. Dosages over 200 mg/day are not recommended. Maintenance therapy is in the range of 50 to 150 mg/day. For convenient therapy and to facilitate patient compliance, the total dosage requirement may be given at bedtime. Hospitalized Patients—Initially, 100 mg/day in divided doses. This may be increased gradually in a few days to 200 mg/day, depending upon individual response and tolerance. If improvement does not occur in 2 to 3 weeks, the dose may be increased to the maximum recommended dose of 250 to 300 mg/day. Adolescent and Geriatric Patients—Initially, a dose of 50 mg/day is recommended, with gradual increments up to 100 mg/day, depending upon patient response and tolerance. 10 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Maintenance—Following remission, maintenance medication may be required for a longer period of time, at the lowest dose that will maintain remission. Maintenance therapy is preferably administered as a single dose at bedtime. To minimize relapse, maintenance therapy should be continued for about three months. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Surmontil. Conversely, at least 14 days should be allowed after stopping Surmontil before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of Surmontil With Other MAOIs, Such as Linezolid or Methylene Blue: Do not start Surmontil in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). In some cases, a patient already receiving therapy with Surmontil may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Surmontil should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Surmontil may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Surmontil is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). OVERDOSAGE* Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital monitoring is required as soon as possible. Manifestations Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, 11 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Management General Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Plasma drug levels may not reflect the severity of the poisoning. Therefore, monitoring of plasma drug levels alone should not guide management of the patient. Gastrointestinal Decontamination All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular A maximal limb-lead QRS duration of ≥ 0.10 seconds has been associated with an increased incidence of seizures. A QRS duration of ≥ 0.16 seconds has been associated with an increased incidence of ventricular dysrhythmias. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/ hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. 12 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Psychiatric Follow-up Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. *Poisindex® Toxicologic Management. Topic: Antidepressants, Tricyclic Micromedex Inc. Vol. 85. HOW SUPPLIED Surmontil® (trimipramine maleate) Capsules 25 mg — Opaque blue and yellow capsule in bottles of 100. Printed OP and 718 50 mg — Opaque blue and orange capsule in bottles of 100. Printed OP and 719. 100 mg — Opaque blue and white capsule in bottles of 100. Printed OP and 720 Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature]. Keep bottles tightly closed. Dispense in a tight container. 13 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:  all risks and benefits of treatment with antidepressant medicines  all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? o Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. o Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. o Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:  thoughts about suicide or dying  attempts to commit suicide  new or worse depression  new or worse anxiety  feeling very agitated or restless 14 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  panic attacks  trouble sleeping (insomnia)  new or worse irritability  acting aggressive, being angry, or violent  acting on dangerous impulses  an extreme increase in activity and talking (mania)  other unusual changes in behavior or mood Who should not take Surmontil?  If you take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.  Do not take an MAOI within 2 weeks of stopping Surmontil unless directed to do so by your physician.  Do not start Surmontil if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. What else do I need to know about antidepressant medicines?  Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.  Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.  Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.  Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.  Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Revised November 2012 15 Nov 30 2012 Version Surmontil – Prior Approval Labeling Supplement Reference ID: 3224127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.314818	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016792s034lbl.pdf', 'application_number': 16792, 'submission_type': 'SUPPL ', 'submission_number': 34}
10,928	NDA 16-851/S-063 Page 3 FML® (fluorometholone ophthalmic suspension, USP) 0.1% sterile DESCRIPTION FML® (fluorometholone ophthalmic suspension, USP) 0.1% is a sterile, topical anti-inflammatory agent for ophthalmic use. Chemical Name Fluorometholone: 9-Fluoro-11ß,17-dihydroxy-6α-methylpregna-1,4-diene-3,20-dione. Structural Formula structural formula Contains Active: fluorometholone 0.1%. Preservative: benzalkonium chloride 0.004%. Inactives: edetate disodium; polysorbate 80; polyvinyl alcohol 1.4%; purified water; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and sodium hydroxide to adjust pH. FML® suspension is formulated with a pH from 6.2 to 7.5. It has an osmolality range of 290-350 mOsm/kg. CLINICAL PHARMACOLOGY Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Corticosteroids are capable of producing a rise in intraocular pressure. In clinical studies of documented steroid-responders, fluorometholone demonstrated a significantly longer average time to produce a rise in intraocular pressure than dexamethasone phosphate; however, in a small Reference ID: 3258813 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-851/S-063 Page 4 percentage of individuals, a significant rise in intraocular pressure occurred within one week. The ultimate magnitude of the rise was equivalent for both drugs. INDICATIONS AND USAGE FML® suspension is indicated for the treatment of corticosteroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe. CONTRAINDICATIONS FML® suspension is contraindicated in most viral diseases of the cornea and conjunctiva, including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye, and fungal diseases of ocular structures. FML® suspension is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids. WARNINGS Prolonged use of corticosteroids may increase intraocular pressure in susceptible individuals, resulting in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in posterior subcapsular cataract formation. Prolonged use may also suppress the host immune response and thus increase the hazard of secondary ocular infections. Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation. Acute purulent infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication. If this product is used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients. Steroids should be used with caution in the presence of glaucoma. Intraocular pressure should be checked frequently. The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is recommended. PRECAUTIONS General The initial prescription and renewal of the medication order beyond 20 milliliters of FML® suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be re-evaluated. Reference ID: 3258813 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-851/S-063 Page 5 As fungal infections of the cornea are particularly prone to develop coincidentally with long-term local corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate. If this product is used for 10 days or longer, intraocular pressure should be monitored (see WARNINGS). Information for Patients If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician. This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children. The preservative in FML® suspension, benzalkonium chloride, may be absorbed by soft contact lenses. Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after instilling FML® suspension to insert soft contact lenses. Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted in animals or in humans to evaluate the possibility of these effects with fluorometholone. Pregnancy Teratogenic effects. Pregnancy Category C Fluorometholone has been shown to be embryocidal and teratogenic in rabbits when administered at low multiples of the human ocular dose. Fluorometholone was applied ocularly to rabbits daily on days 6-18 of gestation, and dose-related fetal loss and fetal abnormalities including cleft palate, deformed rib cage, anomalous limbs and neural abnormalities such as encephalocele, craniorachischisis, and spina bifida were observed. There are no adequate and well-controlled studies of fluorometholone in pregnant women, and it is not known whether fluorometholone can cause fetal harm when administered to a pregnant woman. Fluorometholone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically- administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from fluorometholone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Reference ID: 3258813 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-851/S-063 Page 6 Pediatric Use Safety and effectiveness in infants below the age of two years have not been established. Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients. ADVERSE REACTIONS Adverse reactions include, in decreasing order of frequency, elevation of intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage, posterior subcapsular cataract formation, and delayed wound healing. Although systemic effects are extremely uncommon, there have been rare occurrences of systemic hypercorticoidism after use of topical dermatologic steroids applied to the skin. Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis and perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids. The development of secondary ocular infection (bacterial, fungal and viral) has occurred. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used (see WARNINGS). Transient burning and stinging upon instillation and other minor symptoms of ocular irritation have been reported with the use of FML® suspension. Other adverse events reported with the use of fluorometholone include: allergic reactions; foreign body sensation; erythema of eyelid; eyelid edema/eye swelling; eye discharge; eye pain; eye pruritus; lacrimation increased; rash; taste perversion; visual disturbance (blurry vision); and visual field defect. DOSAGE AND ADMINISTRATION Shake well before using. Instill one drop into the conjunctival sac two to four times daily. During the initial 24 to 48 hours, the dosing frequency may be increased to one application every four hours. Care should be taken not to discontinue therapy prematurely. If signs and symptoms fail to improve after two days, the patient should be re-evaluated (see PRECAUTIONS). The dosing of FML® suspension may be reduced, but care should be taken not to discontinue therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by gradually decreasing the frequency of applications. HOW SUPPLIED: Reference ID: 3258813 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-851/S-063 Page 7 FML® (fluorometholone ophthalmic suspension, USP) 0.1% is supplied sterile in opaque white LDPE plastic bottles with white high impact polystyrene (HIPS) caps as follows: 5 mL in 10 mL bottle - NDC 11980-211-05 10 mL in 15 mL bottle - NDC 11980-211-10 15 mL in 15 mL bottle - NDC 11980-211-15 Storage: Store at 2° - 25°C (36°-77°F); protect from freezing. Store in an upright position. Revised: 02/2013 ©2013 Allergan, Inc. Irvine, CA 92612, U.S.A. ® marks owned by Allergan, Inc. Made in the U.S.A. Reference ID: 3258813 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.338308	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016851s063lbl.pdf', 'application_number': 16851, 'submission_type': 'SUPPL ', 'submission_number': 63}
10,929	CIV DARVON-N® (PROPOXYPHENE NAPSYLATE TABLETS, USP) TABLETS Rx only WARNINGS • There have been numerous cases of accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol. Fatalities within the first hour of overdosage are not uncommon. Many of the propoxyphene related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation. • The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. Patients receiving propoxyphene and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see CLINICAL PHARMACOLOGY – Drug Interactions, WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION for further information). DESCRIPTION Darvon-N contains propoxyphene napsylate, USP which is an odorless, white crystalline powder with a bitter taste. It is very slightly soluble in water and soluble in methanol, ethanol, chloroform, and acetone. Chemically, it is (αS,1R)-α-[2-(Dimethylamino)-1 methylethyl]-α-phenylphenethyl propionate compound with 2-naphthalenesulfonic acid (1:1) monohydrate, which can be represented by the accompanying structural formula. Its molecular weight is 565.72. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Structural Formula Propoxyphene napsylate differs from propoxyphene hydrochloride in that it allows more stable liquid dosage forms and tablet formulations. Because of differences in molecular weight, a dose of 100 mg (176.8 μmol) of propoxyphene napsylate is required to supply an amount of propoxyphene equivalent to that present in 65 mg (172.9 μmol) of propoxyphene hydrochloride. Each tablet of Darvon-N contains 100 mg (176.8 μmol) propoxyphene napsylate. The tablet also contains cellulose, cornstarch, iron oxides, lactose, magnesium stearate, silicon dioxide, stearic acid, and titanium dioxide. CLINICAL PHARMACOLOGY Pharmacology Propoxyphene is a centrally acting opiate analgesic. In vitro studies demonstrated propoxyphene and the metabolite norpropoxyphene inhibit sodium channels (local anesthetic effect) with norpropoxyphene being approximately 2-fold more potent than propoxyphene and propoxyphene approximately 10-fold more potent than lidocaine. Propoxyphene and norpropoxyphene inhibit the voltage-gated potassium current carried by cardiac rapidly activating delayed rectifier (hERG) channels with approximately equal potency. It is unclear if the effects on ion channels occur within therapeutic dose range. Pharmacokinetics Absorption Peak plasma concentrations of propoxyphene are reached in 2 to 2.5 h. After a 65-mg oral dose of propoxyphene hydrochloride, peak plasma levels of 0.05 to 0.1 μg/mL for propoxyphene and 0.1 to 0.2 μg/mL for norpropoxyphene (major metabolite) are achieved. Repeated doses of propoxyphene at 6 h intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 h. Propoxyphene has a half-life of 6 to 12 h, whereas that of norpropoxyphene is 30 to 36 h. Distribution Propoxyphene is about 80% bound to proteins and has a large volume of distribution, 16 L/kg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolism Propoxyphene undergoes extensive first-pass metabolism by intestinal and hepatic enzymes. The major route of metabolism is cytochrome CYP3A4 mediated N demethylation to norpropoxyphene, which is excreted by the kidneys. Ring hydroxylation and glucuronide formation are minor metabolic pathways. Excretion In 48 h, approximately 20 to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene. The renal clearance rate of propoxyphene is 2.6 L/min. SPECIAL POPULATIONS Geriatric Patients After oral administration of propoxyphene in elderly patients (70-78 years), much longer half-lives of propoxyphene and norpropoxyphene have been reported (propropoxyphene 13 to 35 h, norpropoxyphene 22 to 41 h). In addition, the AUC was an average of 3-fold higher and the Cmax was an average of 2.5-fold higher in the elderly when compared to a younger (20-28 years) population. Longer dosage intervals may be considered in the elderly because the metabolism of propoxyphene may be reduced in this patient population. After multiple oral doses of propoxyphene in elderly patients (70-78 years), the Cmax of the metabolite (norpropoxyphene) was increased 5-fold. Pediatric Patients Propoxyphene has not been studied in pediatric patients. Hepatic Impairment No formal pharmacokinetic study of propoxyphene has been conducted in patients with mild, moderate or severe hepatic impairment. After oral administration of propoxyphene in patients with cirrhosis, plasma concentrations of propoxyphene were considerably higher and norpropoxyphene concentrations were much lower than in control patients. This is presumably because of a decreased first-pass metabolism of orally administered propoxyphene in these patients. The AUC ratio of norpropoxyphene: propoxyphene was significantly lower in patients with cirrhosis (0.5 to 0.9) than in controls (2.5 to 4). Renal Impairment No formal pharmacokinetic study of propoxyphene has been conducted in patients with mild, moderate or severe renal impairment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda After oral administration of propoxyphene in anephric patients, the AUC and Cmax values were an average of 76% and 88% greater, respectively. Dialysis removes only insignificant amounts (8%) of administered dose of propoxyphene. Drug Interactions The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. On the other hand, strong CYP3A4 inducers such as rifampin may lead to enhanced metabolite (norpropoxyphene) levels. Propoxyphene is also thought to possess CYP3A4 and CYP2D6 enzyme inhibiting properties. Coadministration with a drug that is a substrate of CYP3A4 or CYP2D6, may result in higher plasma concentrations and increased pharmacologic or adverse effects of that drug. INDICATION Darvon-N is indicated for the relief of mild to moderate pain. CONTRAINDICATIONS Darvon-N is contraindicated in patients with known hypersensitivity to propoxyphene. Darvon-N is contraindicated in patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe asthma or hypercarbia. Darvon-N is contraindicated in any patient who has or is suspected of having paralytic ileus. WARNINGS Risk of Overdose There have been numerous cases of accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol. Fatalities within the first hour of overdosage are not uncommon. Many of the propoxyphene-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Respiratory Depression Respiratory depression is the chief hazard from all opioid agonist preparations. Respiratory depression occurs most frequently in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration. Darvon-N should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of Darvon-N may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. Hypotensive Effect Darvon-N, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Darvon-N may produce orthostatic hypotension in ambulatory patients. Darvon-N, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Drug Interactions The concomitant use of propoxyphene and CNS depressants, including alcohol, can result in potentially serious adverse events including death. Because of its added depressant effects, propoxyphene should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Usage in Ambulatory Patients Propoxyphene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use with Alcohol Patients should be cautioned about the concomitant use of propoxyphene products and alcohol because of potentially serious CNS-additive effects of these agents that can lead to death. PRECAUTIONS Tolerance and Physical Dependence Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy). If Darvon-N is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur (see DRUG ABUSE AND DEPENDENCE). If signs and symptoms of withdrawal occur, patients should be treated by reinstitution of opioid therapy followed by gradual tapered dose reduction of Darvon-N combined with symptomatic support (see DOSAGE AND ADMINISTRATION: Cessation of Therapy). Use in Pancreatic/Biliary Tract Disease Darvon-N may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like Darvon-N may cause increases in the serum amylase level. Hepatic or Renal Impairment Insufficient information exists to make appropriate dosing recommendations regarding the use of either propoxyphene in patients with hepatic or renal impairment as a function of degree of impairment. Higher plasma concentrations and/or delayed elimination may occur in case of impaired hepatic function and/or impaired renal function (see CLINICAL PHARMACOLOGY). If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of propoxyphene metabolites. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Patients/Caregivers 1. Patients should be advised to report pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication. 2. Patients should be advised not to adjust the dose of Darvon-N without consulting the prescribing professional. 3. Patients should be advised that Darvon-N may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). 4. Patients should not combine Darvon-N with central nervous system depressants (e.g., sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur. 5. Patients should be instructed not to consume alcoholic beverages, including prescription and over-the-counter medications that contain alcohol, while using Darvon- N because of risk of serious adverse events including death. 6. Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child. 7. Patients should be advised that Darvon-N is a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. 8. Patients should be advised that if they have been receiving treatment with Darvon-N for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the Darvon-N dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication. Drug Interactions with Propoxyphene Propoxyphene is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when propoxyphene is administered concurrently with agents that affect CYP3A4 activity. The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. Coadministration with agents that induce CYP3A4 activity This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda may reduce the efficacy of propoxyphene. Strong CYP3A4 inducers such as rifampin may lead to enhanced metabolite (norpropoxyphene) levels. Propoxyphene is also thought to possess CYP3A4 and CYP2D6 enzyme inhibiting properties and coadministration with drugs that rely on either of these enzymes for metabolism may result in increased pharmacologic or adverse effects of that drug. Severe neurologic signs, including coma, have occurred with concurrent use of carbamazepine (metabolized by CYP3A4). Increased risk of bleeding has been observed with warfarin-like agents when given along with propoxyphene; however, the mechanistic basis of this interaction is unknown. CNS Depressants Patients receiving narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with propoxyphene may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dosage of Darvon-N. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as Darvon- N. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of Darvon-N and/or may precipitate withdrawal symptoms in these patients. Monoamine Oxidase Inhibitors (MAOIs) MAOIs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant depression of respiration or coma. The use of Darvon- N is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Carcinogenesis, Mutagenesis, Impairment of Fertility The mutagenic and carcinogenic potential of propoxyphene has not been evaluated. In animal studies there was no effect of propoxyphene on mating behavior, fertility, duration of gestation, or parturition when rats were fed propoxyphene as a component of their daily diet at estimated daily propoxyphene intake up to 8-fold greater than the maximum human equivalent dose (HED) based on body surface area comparison. At this highest dose, fetal weight and survival on postnatal day 4 was reduced. Pregnancy Risk summary This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy category C. There are no adequate and well-controlled studies of propoxyphene in pregnant women. While there are limited data in the published literature, adequate animal reproduction studies have not been conducted with propoxyphene. Therefore, it is not known whether propoxyphene can affect reproduction or cause fetal harm when administered to a pregnant woman. Propoxyphene should be given to a pregnant woman only if clearly needed. Clinical considerations Propoxyphene and its major metabolite, norpropoxyphene, cross the human placenta. Neonates whose mothers have taken opiates chronically may exhibit respiratory depression or withdrawal symptoms. Data In published animal reproduction studies, no teratogenic effects occurred in offspring born to pregnant rats or rabbits that received propoxyphene during organogenesis. Pregnant animals received propoxyphene doses approximately 10-fold (rats) and 4-fold (rabbits) the maximum recommended human dose (based on mg/m2 body surface area comparison). Nursing Mothers Propoxyphene, norpropoxyphene (major metabolite), are excreted in human milk. Published studies of nursing mothers using propoxyphene detected no adverse effects in nursing infants. Based on a study of six mother-infant pairs, an exclusively breastfed infant receives approximately 2% of the maternal weight-adjusted dose. Norpropoxyphene is renally excreted and renal clearance is lower in neonates than in adults. Therefore, it is possible that prolonged maternal propoxyphene use could result in norpropoxyphene accumulation in a breastfed infant. Watch breastfeeding infants for signs of sedation including poor feeding, somnolence, or respiratory depression. Caution should be exercised when Darvon-N is administered to a nursing woman. Pediatric Patients Safety and effectiveness in pediatric patients have not been established. Elderly Patients Clinical studies of Darvon-N did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, postmarketing reports suggest that patients over the age of 65 may be more susceptible to CNS-related side effects. Therefore, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Decreased total daily dosage should be considered (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS In hospitalized patients, the most frequently reported were dizziness, sedation, nausea, and vomiting. Other adverse reactions include constipation, abdominal pain, skin rashes, lightheadedness, headache, weakness, euphoria, dysphoria, hallucinations, and minor visual disturbances. The most frequently reported postmarketing adverse events have included completed suicide, accidental and intentional overdose, drug dependence, cardiac arrest, coma, drug ineffective, drug toxicity, nausea, respiratory arrest, cardio-respiratory arrest, death, vomiting, dizziness, convulsion, confusional state, and diarrhea. Additional adverse experiences reported through postmarketing surveillance include: Cardiac disorders: arrhythmia, bradycardia, cardiac/respiratory arrest, congestive arrest, congestive heart failure (CHF), tachycardia, myocardial infarction (MI) Eye disorder: eye swelling, vision blurred General disorder and administration site conditions: drug ineffective, drug interaction, drug tolerance, influenza type illness, drug withdrawal syndrome Gastrointestinal disorder: gastrointestinal bleed, acute pancreatitis Hepatobiliary disorder: hepatic steatosis, hepatomegaly, hepatocellular injury Immune system disorder: hypersensitivity Injury poisoning and procedural complications: drug toxicity, hip fracture, multiple drug overdose, narcotic overdose Investigations: blood pressure decreased, heart rate elevated/abnormal Metabolism and nutrition disorder: metabolic acidosis Nervous system disorder: ataxia, coma, dizziness, somnolence, syncope Psychiatric: abnormal behavior, confusional state, hallucinations, mental status change Respiratory, thoracic, and mediastinal disorders: respiratory depression, dyspnoea Skin and subcutaneous tissue disorder: rash, itch Liver dysfunction has been reported in association with Darvon-N. Propoxyphene therapy has been associated with abnormal liver function tests and, more rarely, with instances of reversible jaundice (including cholestatic jaundice). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Subacute painful myopathy has been reported following chronic propoxyphene overdosage. DRUG ABUSE AND DEPENDENCE Controlled Substance Darvon-N is a Schedule IV narcotic under the U.S. Controlled Substances Act. Darvon-N can produce drug dependence of the morphine type, and therefore, has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration. Darvon-N should be prescribed and administered with the same degree of caution appropriate to the use of other narcotic- containing medications. Abuse Since Darvon-N is a mu-opioid agonist, it may be subject to misuse, abuse, and addiction. Addiction to opioids prescribed for pain management has not been estimated. However, requests for opioids from opioid-addicted patients occur. As such, physicians should take appropriate care in prescribing Darvon-N. Dependence Opioid analgesics may cause psychological and physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug after long term administration. Also, symptoms of withdrawal may be precipitated through the administration of drugs with mu-opioid antagonist activity, e.g., naloxone or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine, dezocine) (see OVERDOSAGE). Physical dependence usually does not occur to a clinically significant degree, until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required to produce the same degree of analgesia, is initially manifested by a shortened duration of an analgesic effect and subsequently, by decreases in the intensity of analgesia. In chronic pain patients, and in opioid-tolerant cancer patients, the administration of Darvon-N should be guided by the degree of tolerance manifested and the doses needed to adequately relieve pain. The severity of the Darvon-N abstinence syndrome may depend on the degree of physical dependence. Withdrawal is characterized by rhinitis, myalgia, abdominal cramping, and occasional diarrhea. Most observable symptoms disappear in 5 to 14 days without treatment; however, there may be a phase of secondary or chronic abstinence which may last for 2 to 6 months characterized by insomnia, irritability, and muscular aches. The patient may be detoxified by gradual This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reduction of the dose. Gastrointestinal disturbances or dehydration should be treated with supportive care. OVERDOSAGE Overdose of Darvon-N may present with the signs and symptoms of propoxyphene overdose. Fatalities within the first hour of overdosage are not uncommon. In all cases of suspected overdosage, call your regional Poison Control Center to obtain the most up-to-date information about the treatment of overdose. This recommendation is made because, in general, information regarding the treatment of overdosage may change more rapidly than do package inserts. Initial consideration should be given to the management of the CNS effects of propoxyphene overdosage. Resuscitative measures should be initiated promptly. Symptoms of Propoxyphene Overdosage The manifestations of acute overdosage with propoxyphene are those of narcotic overdosage. The patient is usually somnolent but may be stuporous or comatose and convulsing. Respiratory depression is characteristic. The ventilatory rate and/or tidal volume is decreased, which results in cyanosis and hypoxia. Pupils, initially pinpoint, may become dilated as hypoxia increases. Cheyne-Stokes respiration and apnea may occur. Blood pressure and heart rate are usually normal initially, but blood pressure falls and cardiac performance deteriorates, which ultimately results in pulmonary edema and circulatory collapse, unless the respiratory depression is corrected and adequate ventilation is restored promptly. Cardiac arrhythmias and conduction delay may be present. A combined respiratory-metabolic acidosis occurs owing to retained CO2 (hypercapnia) and to lactic acid formed during anaerobic glycolysis. Acidosis may be severe if large amounts of salicylates have also been ingested. Death may occur. Treatment of Propoxyphene Overdosage Attention should be directed first to establishing a patent airway and to restoring ventilation. Mechanically assisted ventilation, with or without oxygen, may be required, and positive pressure respiration may be desirable if pulmonary edema is present. The opioid antagonist naloxone will markedly reduce the degree of respiratory depression, and should be administered promptly, preferably intravenously. The duration of action of the antagonist may be brief. If no response is observed after 10 mg of naloxone have been administered, the diagnosis of propoxyphene toxicity should be questioned. In addition to the use of an opioid antagonist, the patient may require careful titration with an anticonvulsant to control convulsions. Activated charcoal can adsorb a significant amount of ingested propoxyphene. Dialysis is of little value in poisoning due to propoxyphene. Efforts should be made to determine whether other agents, such as alcohol, barbiturates, tranquilizers, or other CNS depressants, were also ingested, since these increase CNS depression as well as cause specific toxic effects or death. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Darvon-N is intended for the management of mild to moderate pain. The dose should be individually adjusted according to severity of pain, patient response and patient size. Darvon-N is given orally. The usual dosage is one 100 mg propoxyphene napsylate tablet every 4 hours as needed for pain. The maximum dose of Darvon-N is 6 tablets per day. Do not exceed the maximum daily dose. Patients receiving propoxyphene and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted. Consideration should be given to a reduced total daily dosage in elderly patients and in patients with hepatic or renal impairment. Cessation of Therapy For patients who used Darvon-N on a regular basis for a period of time, when therapy with Darvon-N is no longer needed for the treatment of their pain, it may be useful to gradually discontinue the Darvon-N over time to prevent the development of an opioid abstinence syndrome (narcotic withdrawal). In general, therapy can be decreased by 25% to 50% per day with careful monitoring for signs and symptoms of withdrawal (see DRUG ABUSE AND DEPENDENCE for description of the signs and symptoms of withdrawal). If the patient develops these signs or symptoms, the dose should be raised to the previous level and titrated down more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. HOW SUPPLIED Darvon-N Tablets are available in: The 100 mg tablets are buff colored, elliptical shaped, film coated, and imprinted with the script “DARVON-N 100” on one side of the tablet, using edible black ink. They are available as follows: Bottles of 100 NDC 66479-512-10 Store at 25°C (77°F); excursions are permitted to 15°- 30°C (59°- 86°F) [see USP Controlled Room Temperature]. Inform patients of the availability of a Medication Guide for Darvon/Darvon-N that accompanies each prescription dispensed. Instruct patients to read the Darvon/Darvon- N Medication Guide prior to using Darvon. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Darvon, Darvon-N, Darvocet, and Darvocet-N are registered trademarks of Xanodyne Pharmaceuticals, Inc. © 2009 Xanodyne Pharmaceuticals, Inc. Company logo Newport, KY 41071 PI-512-A REV. 09-2009 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.425930	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016862s041s042lbl.pdf', 'application_number': 16862, 'submission_type': 'SUPPL ', 'submission_number': 42}
10,933	1 NAVANE® Thiothixene Capsules Thiothixene Hydrochloride Concentrate DESCRIPTION Navane® (thiothixene) is a thioxanthene derivative. Specifically, it is the cis isomer of N,N- dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene] thioxanthene-2-sulfonamide. SO2N(CH3)2 C H CH2CH2N N-CH3 S The thioxanthenes differ from the phenothiazines by the replacement of nitrogen in the central ring with a carbon-linked side chain fixed in space in a rigid structural configuration. An N,N- dimethyl sulfonamide functional group is bonded to the thioxanthene nucleus. Inert ingredients for the capsule formulations are: hard gelatin capsules (which contain gelatin and titanium dioxide; may contain Yellow 10, Yellow 6, Blue 1, Green 3, Red 3, and other inert ingredients); lactose; magnesium stearate; sodium lauryl sulfate; starch. Inert ingredients for the oral concentrate formulation are: alcohol; cherry flavor; dextrose; passion fruit flavor; sorbitol solution; water. ACTIONS Navane is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 INDICATIONS Navane is effective in the management of schizophrenia. Navane has not been evaluated in the management of behavioral complications in patients with mental retardation. CONTRAINDICATIONS Navane is contraindicated in patients with circulatory collapse, comatose states, central nervous system depression due to any cause, and blood dyscrasias. Navane is contraindicated in individuals who have shown hypersensitivity to the drug. It is not known whether there is a cross sensitivity between the thioxanthenes and the phenothiazine derivatives, but this possibility should be considered. WARNINGS Tardive Dyskinesia–Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene(1). Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 (For further information about the description of tardive dyskinesia and its clinical detection, please refer to “Information for Patients” in the PRECAUTIONS section, and to the ADVERSE REACTIONS section.) Neuroleptic Malignant Syndrome (NMS)–A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene(2). Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Usage in Pregnancy–Safe use of Navane during pregnancy has not been established. Therefore, this drug should be given to pregnant patients only when, in the judgment of the physician, the expected benefits from the treatment exceed the possible risks to mother and fetus. Animal reproduction studies and clinical experience to date have not demonstrated any teratogenic effects. In the animal reproduction studies with Navane, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. Similar findings have been reported with other psychotropic agents. After repeated oral administration of Navane to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen. Usage in Children–The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. As is true with many CNS drugs, Navane may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, especially during the first few days of therapy. Therefore, the patient should be cautioned accordingly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 As in the case of other CNS-acting drugs, patients receiving Navane (thiothixene) should be cautioned about the possible additive effects (which may include hypotension) with CNS depressants and with alcohol. PRECAUTIONS An antiemetic effect was observed in animal studies with Navane; since this effect may also occur in man, it is possible that Navane may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor. In consideration of the known capability of Navane and certain other psychotropic drugs to precipitate convulsions, extreme caution should be used in patients with a history of convulsive disorders or those in a state of alcohol withdrawal, since it may lower the convulsive threshold. Although Navane potentiates the actions of the barbiturates, the dosage of the anticonvulsant therapy should not be reduced when Navane is administered concurrently. Though exhibiting rather weak anticholinergic properties, Navane should be used with caution in patients who might be exposed to extreme heat or who are receiving atropine or related drugs. Use with caution in patients with cardiovascular disease. Caution as well as careful adjustment of the dosages is indicated when Navane is used in conjunction with other CNS depressants. Also, careful observation should be made for pigmentary retinopathy and lenticular pigmentation (fine lenticular pigmentation has been noted in a small number of patients treated with Navane for prolonged periods). Blood dyscrasias (agranulocytosis, pancytopenia, thrombocytopenic purpura), and liver damage (jaundice, biliary stasis) have been reported with related drugs. Antipsychotic drugs, including thiothixene(3), elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. Information for Patients: Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. Drug Interactions: Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness.(4,5) Due to a possible additive effect with hypotensive agents, patients receiving these drugs should be observed closely for signs of excessive hypotension when thiothixene is added to their drug regimen.(6) ADVERSE REACTIONS NOTE: Not all of the following adverse reactions have been reported with Navane. However, since Navane has certain chemical and pharmacologic similarities to the phenothiazines, all of the known side effects and toxicity associated with phenothiazine therapy should be borne in mind when Navane is used. Cardiovascular Effects: Tachycardia, hypotension, lightheadedness, and syncope. In the event hypotension occurs, epinephrine should not be used as a pressor agent since a paradoxical further lowering of blood pressure may result. Nonspecific EKG changes have been observed in some patients receiving Navane. These changes are usually reversible and frequently disappear on continued Navane therapy. The incidence of these changes is lower than that observed with some phenothiazines. The clinical significance of these changes is not known. CNS Effects: Drowsiness, usually mild, may occur although it usually subsides with continuation of Navane therapy. The incidence of sedation appears similar to that of the piperazine group of phenothiazines but less than that of certain aliphatic phenothiazines. Restlessness, agitation and insomnia have been noted with Navane. Seizures and paradoxical exacerbation of psychotic symptoms have occurred with Navane infrequently. Hyperreflexia has been reported in infants delivered from mothers having received structurally related drugs. In addition, phenothiazine derivatives have been associated with cerebral edema and cerebrospinal fluid abnormalities. Extrapyramidal Symptoms Extrapyramidal symptoms, such as pseudoparkinsonism, akathisia and dystonia have been reported (see Dystonia, Class effect). Management of these extra-pyramidal symptoms depends upon the type and severity. Rapid relief of acute symptoms may require the use of an injectable antiparkinson agent. More slowly emerging symptoms may be managed by reducing the dosage of Navane and/or administering an oral antiparkinson agent. Dystonia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Persistent Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy with thiothixene(1) or may occur after drug therapy has been discontinued. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities. Since early detection of tardive dyskinesia is important, patients should be monitored on an ongoing basis. It has been reported that fine vermicular movement of the tongue may be an early sign of the syndrome. If this or any other presentation of the syndrome is observed, the clinician should consider possible discontinuation of antipsychotic medication. (See WARNINGS section.) Hepatic Effects: Elevations of serum transaminase and alkaline phosphatase, usually transient, have been infrequently observed in some patients. No clinically confirmed cases of jaundice attributable to Navane (thiothixene) have been reported. Hematologic Effects: As is true with certain other psychotropic drugs, leukopenia and leucocytosis, which are usually transient, can occur occasionally with Navane. Other antipsychotic drugs have been associated with agranulocytosis, eosinophilia, hemolytic anemia, thrombocytopenia and pancytopenia. Allergic Reactions: Rash, pruritus, urticaria, photosensitivity and rare cases of anaphylaxis have been reported with Navane. Undue exposure to sunlight should be avoided. Although not experienced with Navane, exfoliative dermatitis and contact dermatitis (in nursing personnel) have been reported with certain phenothiazines. Endocrine/Reproductive: Hyperprolactinemia(3); lactation, menstrual irregularities, moderate breast enlargement and amenorrhea have occurred in a small percentage of females receiving Navane. If persistent, this may necessitate a reduction in dosage or the discontinuation of therapy. Phenothiazines have been associated with false positive pregnancy tests, gynecomastia, hypoglycemia, hyperglycemia and glycosuria. Autonomic Effects: Dry mouth, blurred vision, nasal congestion, constipation, increased sweating, increased salivation and impotence have occurred infrequently with Navane therapy. Phenothiazines have been associated with miosis, mydriasis, and adynamic ileus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Other Adverse Reactions: Hyperpyrexia, anorexia, nausea, vomiting, diarrhea, increase in appetite and weight, weakness or fatigue, polydipsia, and peripheral edema. Although not reported with Navane, evidence indicates there is a relationship between phenothiazine therapy and the occurrence of a systemic lupus erythematosus-like syndrome. Neuroleptic Malignant Syndrome (NMS): Please refer to the text regarding NMS in the WARNINGS section. NOTE: Sudden deaths have occasionally been reported in patients who have received certain phenothiazine derivatives. In some cases the cause of death was apparently cardiac arrest or asphyxia due to failure of the cough reflex. In others, the cause could not be determined nor could it be established that death was due to phenothiazine administration. DOSAGE AND ADMINISTRATION Dosage of Navane should be individually adjusted depending on the chronicity and severity of the symptoms of schizophrenia. In general, small doses should be used initially and gradually increased to the optimal effective level, based on patient response. Some patients have been successfully maintained on once-a-day Navane therapy. The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. In milder conditions, an initial dose of 2 mg three times daily is recommended. If indicated, a subsequent increase to 15 mg/day total daily dose is often effective. In more severe conditions, an initial dose of 5 mg twice daily is recommended. The usual optimal dose is 20 to 30 mg daily. If indicated, an increase to 60 mg/day total daily dose is often effective. Exceeding a total daily dose of 60 mg rarely increases the beneficial response. OVERDOSAGE Manifestations include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma. Treatment: Essentially symptomatic and supportive. Early gastric lavage is helpful. Keep patient under careful observation and maintain an open airway, since involvement of the extrapyramidal system may produce dysphagia and respiratory difficulty in severe overdosage. If hypotension occurs, the standard measures for managing circulatory shock should be used (I.V. fluids and/or vasoconstrictors). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 If a vasoconstrictor is needed, levarterenol and phenylephrine are the most suitable drugs. Other pressor agents, including epinephrine, are not recommended, since phenothiazine derivatives may reverse the usual pressor action of these agents and cause further lowering of blood pressure. If CNS depression is marked, symptomatic treatment is indicated. Extrapyramidal symptoms may be treated with antiparkinson drugs. There are no data on the use of peritoneal or hemodialysis, but they are known to be of little value in phenothiazine intoxication. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 HOW SUPPLIED Navane (thiothixene) Capsules Bottles of 100’s: 1 mg (NDC 0049-5710-66) 2 mg (NDC 0049-5720-66) 5 mg (NDC 0049-5730-66) 10 mg (NDC 0049-5740-66) 20 mg (NDC 0049-5770-66) Rx only LAB-0251-4.0 Revised January 2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 REFERENCES 1. Worldwide Labeling Safety Report: Dyskinesia and Dyskinesia Tardive and Thiothixene, (16Apr02). 2. Worldwide Labeling Safety Report: Neuroleptic Malignant Syndrome and Thiothixene, (16Apr02). 3. Worldwide Labeling Safety Report: Hyperprolactinemia and Thiothixene, (16Apr02). 4. Ereshefsky L, Saklad SR, Watanabe MD, et al. Thiothixene Pharmacokinetic Interactions: A Study of Hepatic Enzyme Inducers, Clearance Inhibitors, and Demographic Variables. Journal of Clinical Psychopharmacology, 11(5):296–301, (1991). 5. Worldwide Labeling Safety Report: Drug Interaction and Thiothixene, (09May02). 6. McEvoy GK, Miller JL, Snow EK, et al. AHFS Drug Information. American Society of Health-System Pharmacists, Inc., p. 2334-2336, (2002). 7. Worldwide Labeling Safety Report: Menstrual Disorder and Thiothixene, (16Apr02). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.586421	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/016584057,016758s019,016904s033lbl.pdf', 'application_number': 16904, 'submission_type': 'SUPPL ', 'submission_number': 33}
10,930	Rx only NDA 16-885/S-023 Page 3 LYSODREN® (mitotane tablets, USP) WARNINGS LYSODREN (mitotane tablets, USP) should be administered under the supervision of a qualified physician experienced in the uses of cancer chemotherapeutic agents. LYSODREN should be temporarily discontinued immediately following shock or severe trauma since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal may not immediately start to secrete steroids. DESCRIPTION LYSODREN® (mitotane tablets, USP) is an oral chemotherapeutic agent. It is best known by its trivial name, o,p'-DDD, and is chemically, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane. The chemical structure is shown below: Structural Formula LYSODREN is a white granular solid composed of clear colorless crystals. It is tasteless and has a slight pleasant aromatic odor. It is soluble in ethanol, isooctane and carbon tetrachloride. It has a molecular weight of 320.05. Inactive ingredients in LYSODREN tablets are: avicel, Polyethylene Glycol 3350, silicon dioxide, and starch. LYSODREN is available as 500 mg scored tablets for oral administration. CLINICAL PHARMACOLOGY LYSODREN can best be described as an adrenal cytotoxic agent, although it can cause adrenal inhibition, apparently without cellular destruction. Its biochemical mechanism of action is unknown. Data are available to suggest that the drug modifies the peripheral metabolism of steroids as well as directly suppressing the adrenal cortex. The administration of LYSODREN alters the extra-adrenal metabolism of cortisol in man; leading to a reduction in measurable 17-hydroxy corticosteroids, even NDA 16-885/S-023 Page 4 though plasma levels of corticosteroids do not fall. The drug apparently causes increased formation of 6-β-hydroxycortisol. Data in adrenal carcinoma patients indicate that about 40% of oral LYSODREN is absorbed and approximately 10% of administered dose is recovered in the urine as a water-soluble metabolite. A variable amount of metabolite (1 to 17%) is excreted in the bile and the balance is apparently stored in the tissues. Following discontinuation of LYSODREN, the plasma terminal half-life has ranged from 18 to 159 days. In most patients blood levels become undetectable after 6 to 9 weeks. Autopsy data have provided evidence that LYSODREN is found in most tissues of the body; however, fat tissues are the primary site of storage. LYSODREN is converted to a water-soluble metabolite. No unchanged LYSODREN has been found in urine or bile. INDICATIONS AND USAGE LYSODREN is indicated in the treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional types. CONTRAINDICATIONS LYSODREN (mitotane tablets, USP) should not be given to individuals who have demonstrated a previous hypersensitivity to it. WARNINGS LYSODREN should be temporarily discontinued immediately following shock or severe trauma, since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal may not immediately start to secrete steroids. LYSODREN should be administered with care to patients with liver disease other than metastatic lesions from the adrenal cortex, since the metabolism of LYSODREN may be interfered with and the drug may accumulate. All possible tumor tissues should be surgically removed from large metastatic masses before LYSODREN administration is instituted. This is necessary to minimize the possibility of infarction and hemorrhage in the tumor due to a rapid cytotoxic effect of the drug. Long-term continuous administration of high doses of LYSODREN may lead to brain damage and impairment of function. Behavioral and neurological assessments should be made at regular intervals when continuous LYSODREN treatment exceeds 2 years. NDA 16-885/S-023 Page 5 A substantial percentage of the patients treated show signs of adrenal insufficiency. It therefore appears necessary to watch for and institute steroid replacement in those patients. However, some investigators have recommended that steroid replacement therapy be administered concomitantly with LYSODREN. It has been shown that the metabolism of exogenous steroids is modified and consequently somewhat higher doses than normal replacement therapy may be required. PRECAUTIONS General Adrenal insufficiency may develop in patients treated with LYSODREN, and adrenal steroid replacement should be considered for these patients. Since sedation, lethargy, vertigo, and other CNS side effects can occur, ambulatory patients should be cautioned about driving, operating machinery, and other hazardous pursuits requiring mental and physical alertness. Drug Interactions LYSODREN has been reported to accelerate the metabolism of warfarin by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for warfarin. Therefore, physicians should closely monitor patients for a change in anticoagulant dosage requirements when administering LYSODREN to patients on coumarin-type anticoagulants. In addition, LYSODREN should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and mutagenic potentials of LYSODREN (mitotane tablets, USP) are unknown. However, the mechanism of action of this compound suggests that it probably has less carcinogenic potential than other cytotoxic chemotherapeutic drugs. Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with LYSODREN. It is also not known whether LYSODREN can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. LYSODREN should be given to a pregnant woman only if clearly needed. Nursing Mothers NDA 16-885/S-023 Page 6 It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from mitotane, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of LYSODREN did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS A very high percentage of patients treated with LYSODREN have shown at least one type of side effect. The main types of adverse reactions consist of the following: 1. Gastrointestinal disturbances, which consist of anorexia, nausea or vomiting, and in some cases diarrhea, occur in about 80% of the patients. 2. Central nervous system side effects occur in 40% of the patients. These consist primarily of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%). 3. Skin toxicity has been observed in about 15% of the cases. These skin changes consist primarily of transient skin rashes which do not seem to be dose related. In some instances, this side effect subsided while the patients were maintained on the drug without a change of dose. Infrequently occurring side effects involve the eye (visual blurring, diplopia, lens opacity, toxic retinopathy); the genitourinary system (hematuria, hemorrhagic cystitis, and albuminuria); cardiovascular system (hypertension, orthostatic hypotension, and flushing); and some miscellaneous effects including generalized aching, hyperpyrexia, and lowered protein bound iodine (PBI). OVERDOSAGE No proven antidotes have been established for LYSODREN overdosage. NDA 16-885/S-023 Page 7 DOSAGE AND ADMINISTRATION The recommended treatment schedule is to start the patient at 2 to 6 g of LYSODREN per day in divided doses, either three or four times a day. Doses are usually increased incrementally to 9 to 10 g per day. If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere. Experience has shown that the maximum tolerated dose (MTD) will vary from 2 to 16 g per day, but has usually been 9 to 10 g per day. The highest doses used in the studies to date were 18 to 19 g per day. Treatment should be instituted in the hospital until a stable dosage regimen is achieved. Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred. If no clinical benefits are observed after 3 months at the maximum tolerated dose, the case would generally be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than 3 months at the MTD. Early diagnosis and prompt institution of treatment improve the probability of a positive clinical response. Clinical effectiveness can be shown by reduction in tumor mass; reduction in pain, weakness or anorexia; and reduction of symptoms and signs due to excessive steroid production. A number of patients have been treated intermittently with treatment being restarted when severe symptoms have reappeared. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggests that continuous treatment with the maximum possible dosage of LYSODREN is the best approach. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 . To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing LYSODREN Tablets. LYSODREN Tablets should not be crushed. Personnel should avoid exposure to crushed and/or broken tablets. If contact with broken tablets occurs, wash immediately and thoroughly. More information is available in the references listed below. HOW SUPPLIED LYSODREN® (mitotane tablets, USP) NDC 0015-3080-60—500 mg Tablets, NDA 16-885/S-023 Page 8 bottle of 100 STORAGE Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193. 4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Made in Italy 1050972A2	custom-source	2025-02-12T13:44:04.644816	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016885s023lbl.pdf', 'application_number': 16885, 'submission_type': 'SUPPL ', 'submission_number': 23}
10,932	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LYSODREN safely and effectively. See full prescribing information for LYSODREN. LYSODREN® (mitotane) tablets, for oral use Initial U.S. Approval: 1970 WARNING: ADRENAL CRISIS IN THE SETTING OF SHOCK OR SEVERE TRAUMA See full prescribing information for complete boxed warning. In patients taking LYSODREN, adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired. Administer hydrocortisone, monitor for escalating signs of shock and discontinue LYSODREN until recovery. (2.2, 5.1) ---------------------------INDICATIONS AND USAGE--------------------------- LYSODREN is an adrenal cytotoxic agent indicated for the treatment of inoperable, functional or nonfunctional, adrenal cortical carcinoma. (1) --------------------------DOSAGE AND ADMINISTRATION-------------------  Initial dose: 2 g to 6 g orally daily, in three or four divided doses. (2.1)  Increase dose incrementally to achieve a blood concentration of 14 to 20 mg/L, or as tolerated. (2.1) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets: 500 mg, scored (3) ------------------------------CONTRAINDICATIONS------------------------------ None (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------  Central Nervous System (CNS) Toxicity: Plasma concentrations exceeding 20 mcg/mL are associated with a greater incidence of toxicity. (5.2)  Adrenal Insufficiency: Institute steroid replacement as clinically indicated. Measure free cortisol and corticotropin (ACTH) levels to achieve optimal steroid replacement. (5.3)  Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.4, 8.1, 8.3) -------------------------------ADVERSE REACTIONS----------------------------- Common adverse reactions (15%) include: anorexia, nausea, vomiting and diarrhea; depression, dizziness or vertigo; and rash. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------ Adjust dosage of concomitant coumarin-type anticoagulants as needed. (7.2) -----------------------USE IN SPECIFIC POPULATIONS-----------------------  Lactation: Do not breastfeed. (8.2)  Hepatic Impairment: Administer LYSODREN with caution to patients with hepatic impairment. (8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 3/2016 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: ADRENAL CRISIS IN THE SETTING OF SHOCK OR SEVERE TRAUMA 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose 2.2 Dose Modifications 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Adrenal Crisis in the Setting of Shock or Severe Trauma 5.2 CNS Toxicity 5.3 Adrenal Insufficiency 5.4 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 CYP3A4 Substrates 7.2 Warfarin 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 3901184 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION WARNING: ADRENAL CRISIS IN THE SETTING OF SHOCK OR SEVERE TRAUMA In patients taking LYSODREN, adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired. Administer hydrocortisone, monitor for escalating signs of shock and discontinue LYSODREN until recovery [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE LYSODREN is indicated for the treatment of patients with inoperable, functional or nonfunctional, adrenal cortical carcinoma. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended initial dose of LYSODREN is 2 g to 6 g orally, in three or four divided doses per day. Increase doses incrementally to achieve a blood concentration of 14 to 20 mg/L, or as tolerated. LYSODREN is a cytotoxic drug. Follow applicable special handling and disposal procedures. 2.2 Dose Modifications Adrenal Crisis in the Setting of Shock or Severe Trauma Discontinue LYSODREN until recovery [see Warnings and Precautions (5.1)]. Central Nervous System (CNS) Toxicity Discontinue LYSODREN until symptoms resolve. Seven to 10 days after symptoms resolve, restart at a lower dose (for example, decrease by 500-1000 mg) [see Warnings and Precautions (5.2)]. 3 DOSAGE FORMS AND STRENGTHS 500 mg white, round, biconvex, scored tablets, bisected on one side and impressed with “BL” over “L1” on the other side. 4 CONTRAINDICATIONS None. Reference ID: 3901184 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 WARNINGS AND PRECAUTIONS 5.1 Adrenal Crisis in the Setting of Shock or Severe Trauma In patients taking LYSODREN, adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired. Administer hydrocortisone, monitor for escalating signs of shock, and discontinue LYSODREN until recovery [see Dosage and Administration (2.2)]. 5.2 CNS Toxicity CNS toxicity, including sedation, lethargy, and vertigo, occurs with LYSODREN treatment. Mitotane plasma concentrations exceeding 20 mcg/mL are associated with a greater incidence of toxicity. 5.3 Adrenal Insufficiency Treatment with LYSODREN can cause adrenal insufficiency. Institute steroid replacement as clinically indicated. Measure free cortisol and corticotropin (ACTH) levels to achieve optimal steroid replacement. 5.4 Embryo-Fetal Toxicity LYSODREN can cause fetal harm when administered to a pregnant woman. Abnormal pregnancy outcomes, such as preterm births and early pregnancy loss, can occur in patients exposed to mitotane during pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LYSODREN and after discontinuation of treatment for as long as mitotane plasma levels are detectable [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label:  Adrenal Crisis in the Setting of Shock or Severe Trauma [see Warnings and Precautions (5.1)]  CNS Toxicity [see Warnings and Precautions (5.2)]  Adrenal Insufficiency [see Warnings and Precautions (5.3)] The following adverse reactions associated with the use of LYSODREN were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Common adverse reactions occurring with LYSODREN treatment include:  Anorexia, nausea, vomiting, and diarrhea (80%)  Depression, dizziness, or vertigo (15%-40%)  Rash (15%) Reference ID: 3901184 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Neutropenia  Growth retardation, hypothyroidism  Confusion, headache, ataxia, mental impairment, weakness, dysarthria  Maculopathy  Hepatitis, elevation of liver enzymes  Gynecomastia  Hypercholesterolemia, hypertriglyceridemia Less common adverse reactions include: visual blurring, diplopia, lens opacity, retinopathy, prolonged bleeding time, hematuria, hemorrhagic cystitis, albuminuria, hypertension, orthostatic hypotension, flushing, generalized aching, and fever. 7 DRUG INTERACTIONS 7.1 CYP3A4 Substrates Mitotane is a strong inducer of cytochrome P450 3A4 (CYP3A4). Monitor patients for a change in dosage requirements for the concomitant drug when administering LYSODREN to patients receiving drugs that are substrates of CYP3A4. 7.2 Warfarin When administering coumarin-type anticoagulants to patients receiving LYSODREN, monitor coagulation tests and adjust the anticoagulant dose as needed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary LYSODREN can cause fetal harm. Limited postmarketing cases report preterm births and early pregnancy loss in women treated with LYSODREN during pregnancy. Animal reproduction studies have not been conducted with mitotane. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 8.2 Lactation Risk Summary Mitotane is excreted in human milk; however, the effect of LYSODREN on the breastfed infant, or effect on milk production is unknown. Because of the potential for serious adverse reactions in the breastfed infant, advise nursing women that breastfeeding is not recommended during Reference ID: 3901184 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula treatment with LYSODREN and after discontinuation of treatment for as long as mitotane plasma levels are detectable. 8.3 Females and Males of Reproductive Potential Contraception Females LYSODREN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with LYSODREN and after discontinuation of therapy for as long as mitotane plasma levels are detectable [see Clinical Pharmacology (12.3)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of LYSODREN did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment Hepatic impairment may interfere with the metabolism of mitotane and the drug may accumulate. Administer LYSODREN with caution to patients with hepatic impairment. 11 DESCRIPTION LYSODREN (mitotane) is an oral adrenal cytotoxic agent. The chemical name is (±)-1,1 dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane (also known as o,p′-DDD). The chemical structure is: Mitotane is a white granular solid composed of clear colorless crystals. It is tasteless and has a slight pleasant aromatic odor. It is soluble in ethanol and has a molecular weight of 320.05. Inactive ingredients in LYSODREN are: microcrystalline cellulose, polyethylene glycol 3350, silicon dioxide, and starch. Reference ID: 3901184 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mitotane is an adrenal cytotoxic agent with an unknown mechanism of action. Mitotane modifies the peripheral metabolism of steroids and directly suppresses the adrenal cortex. A reduction in 17-hydroxycorticosteroids in the absence of decreased corticosteroid concentrations and increased formation of 6--hydroxycortisol have been reported. 12.2 Pharmacodynamics The pharmacodynamics of mitotane are unknown. 12.3 Pharmacokinetics Absorption Following oral administration of LYSODREN, 40% of the dose is absorbed. Distribution Mitotane is found in most tissues of the body; however, fat is the primary site of distribution. Elimination Following discontinuation of mitotane, the plasma terminal half-life ranges from 18 to 159 days (median 53 days). Metabolism Mitotane is converted to a water-soluble metabolite. Excretion No unchanged mitotane is found in urine or bile. Approximately 10% of the administered dose is recovered in the urine as a water-soluble metabolite. A variable amount of metabolite (1%-17%) is excreted in the bile. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenicity and mutagenicity of mitotane are unknown. 15 REFERENCES 1. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html Reference ID: 3901184 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 HOW SUPPLIED/STORAGE AND HANDLING LYSODREN tablets are supplied as 500 mg white, round, biconvex, scored tablets, bisected on one side and impressed with “BL” over “L1” on the other side. 100 tablets per bottle: NDC 0015-3080-60 Store bottles at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F-86°F). Mitotane is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)]. 17 PATIENT COUNSELING INFORMATION Adrenal Crisis  Advise patients to discontinue LYSODREN in the case of shock or severe trauma and contact their healthcare provider immediately.  Advise patients to tell their healthcare provider of any planned surgeries. Embryo-Fetal Toxicity  Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].  Advise females of reproductive potential to use effective contraception during treatment and after discontinuation of treatment for as long as instructed by their healthcare provider [see Use in Specific Populations (8.3)]. Lactation  Advise females who are nursing not to breastfeed during treatment with LYSODREN [see Use in Specific Populations (8.2)]. Manufactured for: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA print code Reference ID: 3901184 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.716195	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016885s026lbl.pdf', 'application_number': 16885, 'submission_type': 'SUPPL ', 'submission_number': 26}
10,934	NAVANE® Thiothixene Capsules Thiothixene Hydrochloride Concentrate WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis— Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Navane is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION Navane® (thiothixene) is a thioxanthene derivative. Specifically, it is the cis isomer of N,N dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene] thioxanthene-2-sulfonamide. structural e le ment The thioxanthenes differ from the phenothiazines by the replacement of nitrogen in the central ring with a carbon-linked side chain fixed in space in a rigid structural configuration. An N,N dimethyl sulfonamide functional group is bonded to the thioxanthene nucleus. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inert ingredients for the capsule formulations are: hard gelatin capsules (which contain gelatin and titanium dioxide; may contain Yellow 10, Yellow 6, Blue 1, Green 3, Red 3, and other inert ingredients); lactose; magnesium stearate; sodium lauryl sulfate; starch. Inert ingredients for the oral concentrate formulation are: alcohol; cherry flavor; dextrose; passion fruit flavor; sorbitol solution; water. ACTIONS Navane is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. INDICATIONS Navane is effective in the management of schizophrenia. Navane has not been evaluated in the management of behavioral complications in patients with mental retardation. CONTRAINDICATIONS Navane is contraindicated in patients with circulatory collapse, comatose states, central nervous system depression due to any cause, and blood dyscrasias. Navane is contraindicated in individuals who have shown hypersensitivity to the drug. It is not known whether there is a cross sensitivity between the thioxanthenes and the phenothiazine derivatives, but this possibility should be considered. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis— Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Navane is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Tardive Dyskinesia–Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene(1). Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to “Information for Patients” in the PRECAUTIONS section, and to the ADVERSE REACTIONS section.) Neuroleptic Malignant Syndrome (NMS)–A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene(2). Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usage in Pregnancy–Safe use of Navane during pregnancy has not been established. Therefore, this drug should be given to pregnant patients only when, in the judgment of the physician, the expected benefits from the treatment exceed the possible risks to mother and fetus. Animal reproduction studies and clinical experience to date have not demonstrated any teratogenic effects. In the animal reproduction studies with Navane, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. Similar findings have been reported with other psychotropic agents. After repeated oral administration of Navane to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen. Usage in Children–The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. As is true with many CNS drugs, Navane may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, especially during the first few days of therapy. Therefore, the patient should be cautioned accordingly. As in the case of other CNS-acting drugs, patients receiving Navane (thiothixene) should be cautioned about the possible additive effects (which may include hypotension) with CNS depressants and with alcohol. PRECAUTIONS An antiemetic effect was observed in animal studies with Navane; since this effect may also occur in man, it is possible that Navane may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor. In consideration of the known capability of Navane and certain other psychotropic drugs to precipitate convulsions, extreme caution should be used in patients with a history of convulsive disorders or those in a state of alcohol withdrawal, since it may lower the convulsive threshold. Although Navane potentiates the actions of the barbiturates, the dosage of the anticonvulsant therapy should not be reduced when Navane is administered concurrently. Though exhibiting rather weak anticholinergic properties, Navane should be used with caution in patients who might be exposed to extreme heat or who are receiving atropine or related drugs. Use with caution in patients with cardiovascular disease. Caution as well as careful adjustment of the dosages is indicated when Navane is used in conjunction with other CNS depressants. Also, careful observation should be made for pigmentary retinopathy and lenticular pigmentation (fine lenticular pigmentation has been noted in a small number of patients treated with Navane 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda for prolonged periods). Blood dyscrasias (agranulocytosis, pancytopenia, thrombocytopenic purpura), and liver damage (jaundice, biliary stasis) have been reported with related drugs. Antipsychotic drugs, including thiothixene(3), elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. Leukopenia, Neutropenia and Agranulocytosis: Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Navane should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Navane and have their WBC followed until recovery. Information for Patients: Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. Drug Interactions: Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness.(4,5) Due to a possible additive effect with hypotensive agents, patients receiving these drugs should be observed closely for signs of excessive hypotension when thiothixene is added to their drug regimen.(6) 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS NOTE: Not all of the following adverse reactions have been reported with Navane. However, since Navane has certain chemical and pharmacologic similarities to the phenothiazines, all of the known side effects and toxicity associated with phenothiazine therapy should be borne in mind when Navane is used. Cardiovascular Effects: Tachycardia, hypotension, lightheadedness, and syncope. In the event hypotension occurs, epinephrine should not be used as a pressor agent since a paradoxical further lowering of blood pressure may result. Nonspecific EKG changes have been observed in some patients receiving Navane. These changes are usually reversible and frequently disappear on continued Navane therapy. The incidence of these changes is lower than that observed with some phenothiazines. The clinical significance of these changes is not known. CNS Effects: Drowsiness, usually mild, may occur although it usually subsides with continuation of Navane therapy. The incidence of sedation appears similar to that of the piperazine group of phenothiazines but less than that of certain aliphatic phenothiazines. Restlessness, agitation and insomnia have been noted with Navane. Seizures and paradoxical exacerbation of psychotic symptoms have occurred with Navane infrequently. Hyperreflexia has been reported in infants delivered from mothers having received structurally related drugs. In addition, phenothiazine derivatives have been associated with cerebral edema and cerebrospinal fluid abnormalities. Extrapyramidal Symptoms Extrapyramidal symptoms, such as pseudoparkinsonism, akathisia and dystonia have been reported (see Dystonia, Class effect). Management of these extra-pyramidal symptoms depends upon the type and severity. Rapid relief of acute symptoms may require the use of an injectable antiparkinson agent. More slowly emerging symptoms may be managed by reducing the dosage of Navane and/or administering an oral antiparkinson agent. Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Persistent Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy with thiothixene(1) or may occur after drug therapy has been discontinued. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities. Since early detection of tardive dyskinesia is important, patients should be monitored on an ongoing basis. It has been reported that fine vermicular movement of the tongue may be an early sign of the syndrome. If this or any other presentation of the syndrome is observed, the clinician should consider possible discontinuation of antipsychotic medication. (See WARNINGS section.) Hepatic Effects: Elevations of serum transaminase and alkaline phosphatase, usually transient, have been infrequently observed in some patients. No clinically confirmed cases of jaundice attributable to Navane (thiothixene) have been reported. Hematologic Effects: As is true with certain other psychotropic drugs, leukopenia and leucocytosis, which are usually transient, can occur occasionally with Navane. Other antipsychotic drugs have been associated with agranulocytosis, eosinophilia, hemolytic anemia, thrombocytopenia and pancytopenia. Allergic Reactions: Rash, pruritus, urticaria, photosensitivity and rare cases of anaphylaxis have been reported with Navane. Undue exposure to sunlight should be avoided. Although not experienced with Navane, exfoliative dermatitis and contact dermatitis (in nursing personnel) have been reported with certain phenothiazines. Endocrine/Reproductive: Hyperprolactinemia(3); lactation, menstrual irregularities, moderate breast enlargement and amenorrhea have occurred in a small percentage of females receiving Navane. If persistent, this may necessitate a reduction in dosage or the discontinuation of therapy. Phenothiazines have been associated with false positive pregnancy tests, gynecomastia, hypoglycemia, hyperglycemia and glycosuria. Autonomic Effects: Dry mouth, blurred vision, nasal congestion, constipation, increased sweating, increased salivation and impotence have occurred infrequently with Navane therapy. Phenothiazines have been associated with miosis, mydriasis, and adynamic ileus. Other Adverse Reactions: Hyperpyrexia, anorexia, nausea, vomiting, diarrhea, increase in appetite and weight, weakness or fatigue, polydipsia, and peripheral edema. Although not reported with Navane, evidence indicates there is a relationship between phenothiazine therapy and the occurrence of a systemic lupus erythematosus-like syndrome. Neuroleptic Malignant Syndrome (NMS): Please refer to the text regarding NMS in the WARNINGS section. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOTE: Sudden deaths have occasionally been reported in patients who have received certain phenothiazine derivatives. In some cases the cause of death was apparently cardiac arrest or asphyxia due to failure of the cough reflex. In others, the cause could not be determined nor could it be established that death was due to phenothiazine administration. DOSAGE AND ADMINISTRATION Dosage of Navane should be individually adjusted depending on the chronicity and severity of the symptoms of schizophrenia. In general, small doses should be used initially and gradually increased to the optimal effective level, based on patient response. Some patients have been successfully maintained on once-a-day Navane therapy. The use of Navane in children under 12 years of age is not recommended because safe conditions for its use have not been established. In milder conditions, an initial dose of 2 mg three times daily is recommended. If indicated, a subsequent increase to 15 mg/day total daily dose is often effective. In more severe conditions, an initial dose of 5 mg twice daily is recommended. The usual optimal dose is 20 to 30 mg daily. If indicated, an increase to 60 mg/day total daily dose is often effective. Exceeding a total daily dose of 60 mg rarely increases the beneficial response. OVERDOSAGE Manifestations include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma. Treatment: Essentially symptomatic and supportive. Early gastric lavage is helpful. Keep patient under careful observation and maintain an open airway, since involvement of the extrapyramidal system may produce dysphagia and respiratory difficulty in severe overdosage. If hypotension occurs, the standard measures for managing circulatory shock should be used (I.V. fluids and/or vasoconstrictors). If a vasoconstrictor is needed, levarterenol and phenylephrine are the most suitable drugs. Other pressor agents, including epinephrine, are not recommended, since phenothiazine derivatives may reverse the usual pressor action of these agents and cause further lowering of blood pressure. If CNS depression is marked, symptomatic treatment is indicated. Extrapyramidal symptoms may be treated with antiparkinson drugs. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There are no data on the use of peritoneal or hemodialysis, but they are known to be of little value in phenothiazine intoxication. HOW SUPPLIED Navane (thiothixene) Capsules Bottles of 100’s: 1 mg (NDC 0049-5710-66) 2 mg (NDC 0049-5720-66) 5 mg (NDC 0049-5730-66) 10 mg (NDC 0049-5740-66) 20 mg (NDC 0049-5770-66) Rx only Pfizer Company Logo LAB-0251-7.0 Revised June 2009 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda REFERENCES 1. Worldwide Labeling Safety Report: Dyskinesia and Dyskinesia Tardive and Thiothixene, (16Apr02). 2. Worldwide Labeling Safety Report: Neuroleptic Malignant Syndrome and Thiothixene, (16Apr02). 3. Worldwide Labeling Safety Report: Hyperprolactinemia and Thiothixene, (16Apr02). 4. Ereshefsky L, Saklad SR, Watanabe MD, et al. Thiothixene Pharmacokinetic Interactions: A Study of Hepatic Enzyme Inducers, Clearance Inhibitors, and Demographic Variables. Journal of Clinical Psychopharmacology, 11(5):296–301, (1991). 5. Worldwide Labeling Safety Report: Drug Interaction and Thiothixene, (09May02). 6. McEvoy GK, Miller JL, Snow EK, et al. AHFS Drug Information. American Society of Health-System Pharmacists, Inc., p. 2334-2336, (2002). 7. Worldwide Labeling Safety Report: Menstrual Disorder and Thiothixene, (16Apr02). 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.777180	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016584s059lbl.pdf', 'application_number': 16904, 'submission_type': 'SUPPL ', 'submission_number': 34}
10,931	LYSODREN® (mitotane tablets, USP) WARNINGS LYSODREN (mitotane tablets, USP) should be administered under the supervision of a qualified physician experienced in the uses of cancer chemotherapeutic agents. LYSODREN should be temporarily discontinued immediately following shock or severe trauma since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal may not immediately start to secrete steroids. DESCRIPTION LYSODREN® (mitotane tablets, USP) is an oral chemotherapeutic agent. It is best known by its trivial name, o,p′-DDD, and is chemically, 1,1-dichloro-2-(o-chlorophenyl)-2-(p chlorophenyl) ethane. The chemical structure is shown below: structural formula LYSODREN is a white granular solid composed of clear colorless crystals. It is tasteless and has a slight pleasant aromatic odor. It is soluble in ethanol, isooctane, and carbon tetrachloride. It has a molecular weight of 320.05. Inactive ingredients in LYSODREN tablets are: avicel, Polyethylene Glycol 3350, silicon dioxide, and starch. LYSODREN is available as 500 mg scored tablets for oral administration. CLINICAL PHARMACOLOGY LYSODREN can best be described as an adrenal cytotoxic agent, although it can cause adrenal inhibition, apparently without cellular destruction. Its biochemical mechanism of action is unknown. Data are available to suggest that the drug modifies the peripheral metabolism of steroids as well as directly suppressing the adrenal cortex. The administration of LYSODREN alters the extra-adrenal metabolism of cortisol in man; leading to a reduction in measurable 17 1 Reference ID: 3407762 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall. The drug apparently causes increased formation of 6-β-hydroxycortisol. Data in adrenal carcinoma patients indicate that about 40% of oral LYSODREN is absorbed and approximately 10% of the administered dose is recovered in the urine as a water-soluble metabolite. A variable amount of metabolite (1%-17%) is excreted in the bile and the balance is apparently stored in the tissues. Following discontinuation of LYSODREN, the plasma terminal half-life has ranged from 18 to 159 days. In most patients blood levels become undetectable after 6 to 9 weeks. Autopsy data have provided evidence that LYSODREN is found in most tissues of the body; however, fat tissues are the primary site of storage. LYSODREN is converted to a water-soluble metabolite. No unchanged LYSODREN has been found in urine or bile. INDICATIONS AND USAGE LYSODREN is indicated in the treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional types. CONTRAINDICATIONS LYSODREN (mitotane tablets, USP) should not be given to individuals who have demonstrated a previous hypersensitivity to it. WARNINGS LYSODREN should be temporarily discontinued immediately following shock or severe trauma, since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal may not immediately start to secrete steroids. LYSODREN should be administered with care to patients with liver disease other than metastatic lesions from the adrenal cortex, since the metabolism of LYSODREN may be interfered with and the drug may accumulate. All possible tumor tissues should be surgically removed from large metastatic masses before LYSODREN administration is instituted. This is necessary to minimize the possibility of infarction and hemorrhage in the tumor due to a rapid cytotoxic effect of the drug. 2 Reference ID: 3407762 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Long-term continuous administration of high doses of LYSODREN may lead to brain damage and impairment of function. Behavioral and neurological assessments should be made at regular intervals, since toxicity may be reversible after discontinuation of LYSODREN. Literature reports suggest that mitotane plasma concentrations exceeding 20 mcg/mL are associated with a greater incidence of high grade central nervous system toxicity. A substantial percentage of the patients treated show signs of adrenal insufficiency. It therefore appears necessary to watch for and institute steroid replacement in those patients. However, some investigators have recommended that steroid replacement therapy be administered concomitantly with LYSODREN. It has been shown that the metabolism of exogenous steroids is modified and consequently somewhat higher doses than normal replacement therapy may be required. Since LYSODREN increases hormone binding proteins, measurement of free cortisol and corticotropin (ACTH) levels may be useful in achieving optimal steroid replacement. PRECAUTIONS General Adrenal insufficiency may develop in patients treated with LYSODREN, and adrenal steroid replacement should be considered for these patients. Since sedation, lethargy, vertigo, and other CNS side effects can occur, ambulatory patients should be cautioned about driving, operating machinery, and other hazardous pursuits requiring mental and physical alertness. Prolonged bleeding time has been reported in patients treated with LYSODREN. Consider this possibility prior to any surgical intervention. Drug Interactions LYSODREN is a strong inducer of cytochrome P-450 3A4 (CYP3A4). Monitor patients for a change in dosage requirements for the concomitant drug when administering LYSODREN to patients receiving drugs that are substrates of CYP3A4. LYSODREN’s CYP induction effect leads to an increase in dosage requirements for warfarin. Closely monitor patients for a change in anticoagulant dosage requirements when administering LYSODREN to patients receiving coumarin-type anticoagulants. 3 Reference ID: 3407762 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and mutagenic potentials of LYSODREN (mitotane tablets, USP) are unknown. However, the mechanism of action of this compound suggests that it probably has less carcinogenic potential than other cytotoxic chemotherapeutic drugs. Pregnancy Pregnancy Category D LYSODERN can cause fetal harm when administered to a pregnant woman. Abnormal pregnancy outcomes such as preterm births and early pregnancy loss have been reported in patients exposed to mitotane during pregnancy. Animal reproduction studies have not been conducted with LYSODREN. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise women of childbearing potential to use effective contraception during treatment and after discontinuation of treatment for as long as mitotane plasma levels are detectable (see CLINICAL PHARMACOLOGY). Nursing Mothers Mitotane has been detected in breast milk. Because of the potential for serious adverse reactions in nursing infants from mitotane, advise women to discontinue nursing during LYSODREN therapy and after treatment discontinuation for as long as mitotane plasma levels are detectable (see CLINICAL PHARMACOLOGY). Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of LYSODREN did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 4 Reference ID: 3407762 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS A very high percentage of patients treated with LYSODREN have shown at least one type of side effect. The main types of adverse reactions consist of the following: 1. Gastrointestinal disturbances, which consist of anorexia, nausea or vomiting, and in some cases diarrhea, occur in about 80% of the patients. 2. Central nervous system side effects occur in 40% of the patients. These consist primarily of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%). 3. Skin toxicity has been observed in about 15% of the cases. These skin changes consist primarily of transient skin rashes which do not seem to be dose related. In some instances, this side effect subsided while the patients were maintained on the drug without a change of dose. Infrequently occurring side effects involve the eye (visual blurring, diplopia, lens opacity, toxic retinopathy); the genitourinary system (hematuria, hemorrhagic cystitis, and albuminuria); cardiovascular system (hypertension, orthostatic hypotension, and flushing); and some miscellaneous effects including generalized aching, hyperpyrexia, and lowered protein bound iodine (PBI). The following additional adverse reactions have been identified during postapproval use of LYSODREN. Because reports are voluntary from a population of unknown size, an estimate of frequency cannot be made. Blood and lymphatic system disorders: neutropenia Endocrine disorders: growth retardation, hypothyroidism Psychiatric disorders: confusional state Nervous system disorders: neuropsychological disturbance, dysarthria, headache, ataxia, mental impairment Eye disorders: maculopathy Hepatobiliary disorders: hepatitis, elevation of liver enzymes Reproductive system and breast disorders: gynecomastia 5 Reference ID: 3407762 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda General disorders and administration site conditions: asthenia Investigations: blood uric acid decreased, blood cholesterol increased, blood triglycerides increased OVERDOSAGE No proven antidotes have been established for LYSODREN overdosage. The long half-life of mitotane will require prolonged observation for toxicity (see CLINICAL PHARMACOLOGY). DOSAGE AND ADMINISTRATION The recommended treatment schedule is to start the patient at 2 g to 6 g of LYSODREN per day in divided doses, either 3 or 4 times a day. Doses are usually increased incrementally to 9 g to 10 g per day. If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere. Experience has shown that the maximum tolerated dose (MTD) will vary from 2 g to 16 g per day, but has usually been 9 g to 10 g per day. The highest doses used in the studies to date were 18 g to 19 g per day. Treatment should be instituted in the hospital until a stable dosage regimen is achieved. Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred. If no clinical benefits are observed after 3 months at the maximum tolerated dose, the case would generally be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than 3 months at the MTD. Early diagnosis and prompt institution of treatment improve the probability of a positive clinical response. Clinical effectiveness can be shown by reduction in tumor mass; reduction in pain, weakness or anorexia; and reduction of symptoms and signs due to excessive steroid production. A number of patients have been treated intermittently with treatment being restarted when severe symptoms have reappeared. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggests that continuous treatment with the maximum possible dosage of LYSODREN is the best approach. 6 Reference ID: 3407762 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1 To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing LYSODREN tablets. LYSODREN tablets should not be crushed. Personnel should avoid exposure to crushed and/or broken tablets. If contact with broken tablets occurs, wash immediately and thoroughly. More information is available in the references listed below. HOW SUPPLIED LYSODREN® (mitotane tablets, USP) NDC 0015-3080-60—500 mg Tablets, bottle of 100 STORAGE Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. REFERENCES 1. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html Manufactured for: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Made in Italy Rev November 2013 7 Reference ID: 3407762 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.865924	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016885s025lbl.pdf', 'application_number': 16885, 'submission_type': 'SUPPL ', 'submission_number': 25}
10,935	RETIN-A® Cream Gel Liquid (tretinoin) For Topical Use Only Prescribing Information Description: RETIN-A Gel, Cream, and Liquid, containing tretinoin are used for the topical treatment of acne vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or 0.01% by weight, in a gel vehicle of butyl alcohol, hydroxypropyl cellulose and alcohol (denatured with tert- butylated hydroxytoluene, and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid and has the following structure: Leave space for structure. Clinical Pharmacology: Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. Indications and Usage: RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the long-term use of this product in the treatment of other disorders have not been established. Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is noted. Warnings: GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Precautions: General: If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN- A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of RETIN-A is begun. Carcinogenesis, Mutagenesis, Impairment to Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light form a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with RETIN-A has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical does adjusted for total body surface area). Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic does adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic does adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of RETIN-A. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic effects: Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RETIN-A is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established. Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions: The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of therapy (see Dosage and Administration Section). Overdosage: If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. Dosage and Administration: RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: the liquid may be applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it, to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient. Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less frequent applications, or other dosage forms. Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be cleansed thoroughly before the medication is applied. (See Precautions) How Supplied: RETIN-A (tretinoin) is supplied as: RETIN-A Cream NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0165-01 0.025% Cream 20g 0062-0165-02 0.025% Cream 45g 0062-0175-12 0.05% Cream 20g 0062-0175-13 0.05% Cream 45g 0062-0275-23 0.1% Cream 20g 0062-0275-01 0.1% Cream 45g RETIN-A Gel NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0575-44 0.01% Gel 15g 0062-0575-46 0.01% Gel 45g 0062-0475-42 0.025% Gel 15g 0062-0475-45 0.025% Gel 45g RETIN-A Liquid NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0075-07 0.05% Liquid 28 mL Storage Conditions: RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN- A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RETIN-A® PATIENT INSTRUCTIONS Cream Gel Liquid (tretinoin) Acne Treatment For Topical Use Only IMPORTANT Read Directions Carefully Before Using THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. WARNINGS RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). PRECAUTIONS The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you do become sunburned, stop your therapy with RETIN-A until your skin has recovered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or crusted. If you are experiencing severe or persistent irritation, discontinues the use of RETIN-A and consult your physician. There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when the skin was allowed to adjust to RETIN-A or therapy was discontinued. Use other medication only on your physician’s advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and hair permanent solutions. Do not allow anyone else to use this medication. Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you have used in the past might cause unnecessary redness or peeling. If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are nursing a baby, consult your physician before using the medication. AND WHILE YOU’RE ON RETIN-A THERAPY Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be sufficient). Pat skin dry with a towel. Let the face dry 20-30 minutes before applying RETIN-A. Remember, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician, etc., may worsen your acne. HOW TO USE RETIN-A (TRETINOIN) To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN, FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF YOU HAVE QUESTIONS, ASK YOU DOCTOR. To help you use the medication correctly, keep these simple instructions in mind. (Insert picture) • Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise, especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First, wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation. • It is better not to use more than the amount suggested by your physician or to apply more frequently than instructed. Too much may irritate the skin, waste medication and won’t give faster or better results. • Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from these areas when applying. • RETIN-A Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin cream) Cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. • RETIN-A Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin gel) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected are. Smooth gently into the skin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • RETIN-A Liquid. RETIN-A (tretinoin liquid) Liquid may be applied to the skin where acne lesions appear, spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into area where treatment is not intended (such as corners of the mouth, eyes, and nose). • It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage it is important to continue using RETIN-A. If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop treatment at the first signs of improvement. Once your acne is under control you should continue regular application of RETIN-A until your physician instructs otherwise. IF YOU HAVE QUESTIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A (tretinoin), call our toll-free number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday through Friday. Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Markham Luke 6/10/02 11:40:52 AM Acting for Dr. Jonathan Wilkin, Division Director, DDDDP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:04.993577	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf', 'application_number': 16921, 'submission_type': 'SUPPL ', 'submission_number': 22}
10,937	NDA 16-931/S-028 Page 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-931/S-028 Page 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-931/S-028 Page 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-931/S-028 Page 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-931/S-028 Page 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-931/S-028 Page 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:05.062030	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/16931slr028_r-gene_lbl.pdf', 'application_number': 16931, 'submission_type': 'SUPPL ', 'submission_number': 28}
10,936	RETIN-A® Cream Gel Liquid (tretinoin) For Topical Use Only Prescribing Information Description: RETIN-A Gel, Cream, and Liquid, containing tretinoin are used for the topical treatment of acne vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or 0.01% by weight, in a gel vehicle of butyl alcohol, hydroxypropyl cellulose and alcohol (denatured with tert- butylated hydroxytoluene, and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid and has the following structure: Leave space for structure. Clinical Pharmacology: Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. Indications and Usage: RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the long-term use of this product in the treatment of other disorders have not been established. Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is noted. Warnings: GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Precautions: General: If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN- A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of RETIN-A is begun. Carcinogenesis, Mutagenesis, Impairment to Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light form a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with RETIN-A has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical does adjusted for total body surface area). Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic does adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic does adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of RETIN-A. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic effects: Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RETIN-A is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established. Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions: The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of therapy (see Dosage and Administration Section). Overdosage: If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. Dosage and Administration: RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: the liquid may be applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it, to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient. Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less frequent applications, or other dosage forms. Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be cleansed thoroughly before the medication is applied. (See Precautions) How Supplied: RETIN-A (tretinoin) is supplied as: RETIN-A Cream NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0165-01 0.025% Cream 20g 0062-0165-02 0.025% Cream 45g 0062-0175-12 0.05% Cream 20g 0062-0175-13 0.05% Cream 45g 0062-0275-23 0.1% Cream 20g 0062-0275-01 0.1% Cream 45g RETIN-A Gel NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0575-44 0.01% Gel 15g 0062-0575-46 0.01% Gel 45g 0062-0475-42 0.025% Gel 15g 0062-0475-45 0.025% Gel 45g RETIN-A Liquid NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0075-07 0.05% Liquid 28 mL Storage Conditions: RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN- A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RETIN-A® PATIENT INSTRUCTIONS Cream Gel Liquid (tretinoin) Acne Treatment For Topical Use Only IMPORTANT Read Directions Carefully Before Using THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. WARNINGS RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). PRECAUTIONS The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you do become sunburned, stop your therapy with RETIN-A until your skin has recovered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or crusted. If you are experiencing severe or persistent irritation, discontinues the use of RETIN-A and consult your physician. There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when the skin was allowed to adjust to RETIN-A or therapy was discontinued. Use other medication only on your physician’s advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and hair permanent solutions. Do not allow anyone else to use this medication. Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you have used in the past might cause unnecessary redness or peeling. If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are nursing a baby, consult your physician before using the medication. AND WHILE YOU’RE ON RETIN-A THERAPY Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be sufficient). Pat skin dry with a towel. Let the face dry 20-30 minutes before applying RETIN-A. Remember, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician, etc., may worsen your acne. HOW TO USE RETIN-A (TRETINOIN) To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN, FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF YOU HAVE QUESTIONS, ASK YOU DOCTOR. To help you use the medication correctly, keep these simple instructions in mind. (Insert picture) • Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise, especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First, wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation. • It is better not to use more than the amount suggested by your physician or to apply more frequently than instructed. Too much may irritate the skin, waste medication and won’t give faster or better results. • Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from these areas when applying. • RETIN-A Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin cream) Cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. • RETIN-A Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin gel) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected are. Smooth gently into the skin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • RETIN-A Liquid. RETIN-A (tretinoin liquid) Liquid may be applied to the skin where acne lesions appear, spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into area where treatment is not intended (such as corners of the mouth, eyes, and nose). • It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage it is important to continue using RETIN-A. If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop treatment at the first signs of improvement. Once your acne is under control you should continue regular application of RETIN-A until your physician instructs otherwise. IF YOU HAVE QUESTIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A (tretinoin), call our toll-free number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday through Friday. Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Markham Luke 6/10/02 11:40:52 AM Acting for Dr. Jonathan Wilkin, Division Director, DDDDP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:05.063623	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf', 'application_number': 16921, 'submission_type': 'SUPPL ', 'submission_number': 25}
10,938	R-Gene® 10 Arginine Hydrochloride Injection, USP For Intravenous Use DESCRIPTION Each 100 mL of R-Gene® 10 (Arginine Hydrochloride Injection, USP) for intravenous use contains 10 g of L-Arginine Hydrochloride, USP in Water for Injection, USP (equivalent to a 10% solution). L-arginine is a naturally occurring amino acid. R-Gene® 10 is hypertonic (950 mOsmol/liter) and contains 47.5 mEq of chloride ion per 100 mL of solution. The pH is adjusted to 5.6 (5.0-6.5) with arginine base or hydrochloric acid. CLINICAL PHARMACOLOGY Intravenous infusion of R-Gene® 10 often induces a pronounced rise in the plasma level of human growth hormone (HGH) in subjects with intact pituitary function. This rise is usually diminished or absent in patients with impairment of this function. Expected Plasma Levels of HGH in ng/mL Range of Patient Normal Control Range 0-6 Peak Response to Arginine 10-30 Pituitary deficient 0-4 0-10 These ranges are based on the mean values of plasma HGH levels calculated from the data of several clinical investigators and reflect their experiences with various methods of radioimmunoassay. Upon gaining experience with this diagnostic test, each clinician will establish his/her own ranges for control and peak levels of HGH. L-arginine is a normal metabolite in animals and man and has a low order of toxicity. INDICATIONS AND USAGE R-Gene® 10 is indicated as an intravenous stimulant to the pituitary for the release of human growth hormone in patients where the measurement of pituitary reserve for HGH can be of diagnostic usefulness. It can be used as a diagnostic aid in such conditions as panhypopituitarism, pituitary dwarfism, chromophobe adenoma, postsurgical craniopharyngioma, hypophysectomy, pituitary trauma, acromegaly, gigantism and problems of growth and stature. If the insulin hypoglycemia test has indicated a deficiency of pituitary reserve for HGH, a test with R-Gene® 10 is advisable to confirm the negative response. This can be done after a waiting period of one day. As patients may not respond to R-Gene® 10 (Arginine Hydrochloride Injection, USP) during the first test, the unresponsive patient should be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda tested again to confirm the negative result. A second test can be performed after a waiting period of one day. Some patients who respond to R-Gene® 10 do not respond to insulin and vice versa. The rate of false positive responses for R-Gene® 10 is approximately 32%, and the rate of false negatives is approximately 27%. CONTRAINDICATIONS The administration of R-Gene® 10 is contraindicated in persons having known hypersensitivity to any ingredient in this product. WARNINGS There have been reports of overdosage of R-Gene® 10 in pediatric patients leading to death. EXTREME CAUTION MUST BE EXERCISED WHEN INFUSING R-GENE® 10 INTO PEDIATRIC PATIENTS. OVERDOSAGE OF R-GENE® 10 IN PEDIATRIC PATIENTS CAN RESULT IN HYPERCHLOREMIC METABOLIC ACIDOSIS, CEREBRAL EDEMA, OR POSSIBLY DEATH. Hypersensitivity reactions, including anaphylaxis have been reported. Appropriate medical support should be available during R-Gene 10 administration. If anaphylaxis or other serious hypersensitivity reaction occurs, R-Gene 10 should be discontinued and appropriate medical treatment initiated. R-Gene® 10 should always be administered by intravenous infusion because of its hypertonicity. R-Gene® 10 is a diagnostic aid and is not intended for therapeutic use. PRECAUTIONS General R-Gene® 10 is a hypertonic (950 mOsmol/liter) and acidic (average pH of 5.6) solution that can cause irritation and damage to tissues. Care should be used to ensure administration of R-Gene® 10 through a patent catheter within a patent vein. Excessive rates of infusion may result in local irritation and in flushing, nausea, or vomiting. Inadequate dosing or prolongation of the infusion period may diminish the stimulus to the pituitary and nullify the test. The arginine in R-Gene® 10 can be metabolized resulting in nitrogen-containing products for excretion. The effect of an acute amino acid or nitrogen burden upon patients with impairment of renal function should be considered when R-Gene® 10 is to be administered. The chloride content of R-Gene® 10 is 47.5 mEq per 100 mL of solution, and the effect of infusing this amount of chloride into patients with electrolyte imbalance should be evaluated before the test is undertaken. It should be noted that the basal and post stimulation levels of growth hormone are elevated in patients who are pregnant or are taking oral contraceptives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, and impairment of fertility Long term animal studies have not been performed to evaluate the carcinogenic potential, the mutagenic potential or the effect on fertility of intravenously administered R-Gene® 10. Pregnancy Category B Reproduction studies have been performed in rabbits and mice at doses 12 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to R-Gene® 10 (10% Arginine Hydrochloride Injection, USP). There have been no adequate or well controlled studies for the use of R-Gene® 10 in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy. Nursing Mothers It is not known whether intravenous administration of R-Gene® 10 could result in significant quantities of arginine in breast milk. Systemically administered amino acids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when R-Gene® 10 is to be administered to nursing women. Geriatric Use Clinical studies of arginine did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. ADVERSE REACTIONS Adverse reactions associated with 1670 infusions in premarketing studies were as follows: Non-specific side effects consisting of nausea, vomiting, headache, flushing, numbness and local venous irritation were reported in approximately 3% of the patients. One patient had an allergic reaction which was manifested as a confluent macular rash with reddening and swelling of the hands and face. The rash subsided rapidly after the infusion was terminated and 50 mg of diphenhydramine were administered. One patient had an apparent decrease in platelet count from 150,000 to 60,000. One patient with a history of acrocyanosis had an exacerbation of this condition following infusion of R- Gene® 10. Post Marketing Experience: The following adverse events have been reported during post-marketing use: extravasation leading to burn-like reaction and/or skin necrosis requiring surgical intervention, hypersensitivity reactions including anaphylaxis, and hematuria that in some cases occurred 1-2 days after an R-Gene 10 administration. Because these adverse events This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. OVERDOSAGE An overdosage may cause a transient metabolic acidosis with hyperventilation which could lead to death (See “WARNINGS”). In most cases the acidosis will self-compensate and the base deficit will return to normal following completion of the infusion. If the condition persists, the deficit should be determined and corrected by a calculated dose of an alkalizing agent. DOSAGE AND ADMINISTRATION Adult Dosage The recommended adult dose is 30 g arginine hydrochloride (300 mL of R-Gene® 10) administered by intravenous infusion over 30 minutes. The total dose should not exceed 30 g arginine hydrochloride. See Directions for Use for preparation instructions. Pediatric Dosage The recommended pediatric dose is 0.5 g/kg arginine hydrochloride (5 mL/kg of R- Gene® 10) administered by intravenous infusion over 30 minutes. The total dose should not exceed 30 g arginine hydrochloride. • For patients weighing 59 kg or less, withdraw a weight based dose from a sealed R- Gene® 10 bottle and place in a separate container for intravenous infusion to avoid the inadvertent delivery and administration of the total volume from the commercially available container. See Directions for Use for preparation instructions. • For patients weighing 60 kg or more, the recommended dose is 30 g arginine hydrochloride (300 mL of R-Gene® 10). See Directions for Use for preparation instructions Test Procedure The intravenous infusion of R-Gene® 10 is a part of the test for measurement of pituitary reserve of human growth hormone and, for successful administration of the test, clinical conditions and procedures should be as follows: 1. The test should be scheduled in the morning following a normal night’s sleep, and an overnight fast should continue through the test period. 2. Patients must be placed at bed rest for at least 30 minutes before the infusion begins. Care should be taken to minimize apprehension and distress. This is particularly important in children. 3. R-Gene® 10 (Arginine Hydrochloride Injection, USP) is a hypertonic solution and should only be infused through an indwelling needle or soft catheter placed in an antecubital vein or other suitable vein (See PRECAUTIONS). Blood samples should be taken by venipuncture from the contra-lateral arm. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4. A desirable schedule for drawing blood samples is at –30, 0, 30, 60, 90, 120 and 150 minutes. 5. R-Gene® 10 should be infused beginning at zero time at a uniform rate which will permit the recommended dose to be administered over 30 minutes. 6. Blood samples should be promptly centrifuged and the plasma stored at –20°C until assayed by one of the published radioimmunoassay procedures. 7. Diagnostic test results showing a deficiency of pituitary reserve for HGH should be confirmed by a second test with R-Gene® 10, or one may elect to confirm with the insulin hypoglycemia test. A waiting period of one day is advised between tests. Directions for Use R-Gene® 10 is provided as a ready-to-use solution for patients weighing 60 kg (132 lbs) or more and should not be further diluted. For pediatric patients weighing 59 kg (130 lbs) or less a dose must be placed in a separate container. Follow the preparation instructions below. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. For Pediatric Patients weighing 59 kg (130 lbs) or less: Withdraw a weight-based dose from an intact sealed bottle of R-Gene® 10. The entire 300 mL bottle of R-Gene® 10 for infusion is not intended for use in patients weighing 59 kg or less. The dose must be placed in a separate container, such as an evacuated sterile glass container designed for intravenous administration, using aseptic technique. Additionally, R-Gene® 10 is stable in polypropylene syringes and plastic containers made of either polyvinyl chloride (PVC) or ethylene vinyl acetate (EVA). The post-penetration storage period is not more than 4 hours at room temperature or 24 hours at refrigerated temperature (2-8°C). The healthcare professional administering the dose should berify the accuracy of the dose prior to administration. Use only if the solution is clear. Discard any unused drug product. For Adults and Pediatric Patients weighing 60kg (132 lbs) or more: Follow these directions using aseptic technique. As R-Gene® 10 for intravenous use is provided in glass containers, a standard air-inletting, air-filtering intravenous infusion set with a bacterial air filter is required. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1. Use only if solution is clear and seal is intact. Carefully examine bottle for evidence of damage, e.g., dents or other evidence of damage to metal cap, small cracks, dents in seal, or areas of dried powder on exterior. Do not administer contents if such damage is found. 2. Remove tamperproof metal seal and metal disc from bottle to expose rubber stopper, taking care that you do not contaminate the target site of the stopper with fingers, hair, clothing, etc. Immediately perform step #3. 3. With shut-off clamp closed, remove sterility protector from spike of administration set and immediately insert set with a quick thrust into center of stopper with bottle upright on table. (Push straight in — don’t twist — twisting may cause stopper coring.) 4. Promptly invert bottle to automatically establish fluid level in drip chamber and to check for vacuum by observing rising filtered air bubbles. Discard bottle if there is no vacuum or if the solution is not clear. 5. Clear tubing of air. Proceed with infusion. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usage Illustrations This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED R-Gene® 10 is supplied as a 300 mL fill in 500 mL glass containers. Preservative Free: Discard any unused portion. NDC 0009-0436-24 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at room temperature (25°C); however, brief exposure up to 40°C does not adversely affect the product. Solution that has been frozen must not be used. Rx Only Company logo Manufactured By: Hospira, Inc. Lake Forest, IL 60045 USA LAB-0020-5.0 Revised June 2009 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:05.188154	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/016931s031lbl.pdf', 'application_number': 16931, 'submission_type': 'SUPPL ', 'submission_number': 31}
10,940	ORTHO MICRONOR® Tablets (norethindrone) Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. DESCRIPTION ORTHO MICRONOR® Tablets Each tablet contains 0.35 mg norethindrone. Inactive ingredients include corn starch, D&C Green No. 5 , D&C Yellow No. 10, lactose, magnesium stearate, and povidone. Chemical Structure norethindrone CLINICAL PHARMACOLOGY 1. Mode of Action ORTHO MICRONOR® progestin-only oral contraceptives prevent conception by suppressing ovulation in approximately half of users, thickening the cervical mucus to inhibit sperm penetration, lowering the midcycle LH and FSH peaks, slowing the movement of the ovum through the fallopian tubes, and altering the endometrium. 2. Pharmacokinetics Serum progestin levels peak about two hours after oral administration, followed by rapid distribution and elimination. By 24 hours after drug ingestion, serum levels are near baseline, making efficacy dependent upon rigid adherence to the dosing schedule. There are large variations in serum levels among individual users. Progestin-only administration results in lower steady-state serum progestin levels and a shorter elimination half-life than concomitant administration with estrogens. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE 1. Indications Progestin-only oral contraceptives are indicated for the prevention of pregnancy. 2. Efficacy If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. Table 1 lists the pregnancy rates for users of all major methods of contraception. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. % of Women Experiencing an % of Women Unintended Pregnancy within the First Year of Use Continuing Use at One Year3 Method Typical Use 1 Perfect Use2 Chance4 (1) (2) 85 (3) 85 (4) Spermicides5 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal6 2 Post-Ovulation 1 Cap7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women Diaphragm7 20 20 9 6 56 56 Withdrawal 19 4 Condom8 Female (Reality®) 21 5 56 Male 14 3 61 Pill 5 71 Progestin Only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera® 0.3 0.3 70 Norplant® and 0.05 0.05 88 Norplant-2® Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Adapted from Hatcher et al, 1998, Ref. # 1. Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9 Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraception.10 Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. 1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. 4 The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 5 Foams, creams, gels, vaginal suppositories, and vaginal film. 6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7 With spermicidal cream or jelly. 8 Without spermicides. 9 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light-orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills). 10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age. ORTHO MICRONOR® Tablets have not been studied for and are not indicated for use in emergency contraception. CONTRAINDICATIONS Progestin-only oral contraceptives (POPs) should not be used by women who currently have the following conditions: • Known or suspected pregnancy • Known or suspected carcinoma of the breast • Undiagnosed abnormal genital bleeding • Hypersensitivity to any component of this product • Benign or malignant liver tumors • Acute liver disease WARNINGS Cigarette smoking increases the risk of serious cardiovascular d isease. Women who use oral contraceptives should be strongly advised not to smoke. ORTHO MICRONOR® does not contain estrogen and, therefore, this insert does not discuss the serious health risks that have been associated with the estrogen component of combined oral contraceptives (COCs). The healthcare professional is referred to the prescribing information of combined oral contraceptives for a discussion of those risks. The relationship between progestin-only oral contraceptives and these risks is not fully defined. The healthcare professional should remain alert to the earliest manifestation of symptoms of any serious disease and discontinue oral contraceptive therapy when appropriate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1. Ectopic Pregnancy The incidence of ectopic pregnancies for progestin-only oral contraceptive users is 5 per 1000 woman-years. Up to 10% of pregnancies reported in clinical studies of progestin-only oral contraceptive users are extrauterine. Although symptoms of ectopic pregnancy should be watched for, a history of ectopic pregnancy need not be considered a contraindication to use of this contraceptive method. Healthcare professionals should be alert to the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain while on progestin-only oral contraceptives. 2. Delayed Follicular Atresia/Ovarian Cysts If follicular development occurs, atresia of the follicle is sometimes delayed and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally these enlarged follicles disappear spontaneously. Often they are asymptomatic; in some cases they are associated with mild abdominal pain. Rarely they may twist or rupture, requiring surgical intervention. 3. Irregular Genital Bleeding Irregular menstrual patterns are common among women using progestin-only oral contraceptives. If genital bleeding is suggestive of infection, malignancy or other abnormal conditions, such nonpharmacologic causes should be ruled out. If prolonged amenorrhea occurs, the possibility of pregnancy should be evaluated. 4. Carcinoma of the Breast and Reproductive Organs Some epidemiological studies of oral contraceptive users have reported an increased relative risk of developing breast cancer, particularly at a younger age and apparently related to duration of use. These studies have predominantly involved combined oral contraceptives and there is insufficient data to determine whether the use of POPs similarly increases the risk. A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use. Women with breast cancer should not use oral contraceptives because the role of female hormones in breast cancer has not been fully determined. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. There is insufficient data to determine whether the use of POPs increases the risk of developing cervical intraepithelial neoplasia. 5. Hepatic Neoplasia Benign hepatic adenomas are associated with combined oral contraceptive use, although the incidence of benign tumors is rare in the United States. Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in combined oral contraceptive users. However, these cancers are rare in the U.S. There is insufficient data to determine whether POPs increase the risk of developing hepatic neoplasia. PRECAUTIONS 1. General Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 2. Physical Examination and Follow up It is considered good medical practice for sexually active women using oral contraceptives to have annual history and physical examinations. The physical examination may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the healthcare professional. 3. Carbohydrate and Lipid Metabolism Some users may experience slight deterioration in glucose tolerance, with increases in plasma insulin but women with diabetes mellitus who use progestin-only oral contraceptives do not generally experience changes in their insulin requirements. Nonetheless, prediabetic and diabetic women in particular should be carefully monitored while taking POPs. Lipid metabolism is occasionally affected in that HDL, HDL2, and apolipoprotein A-I and A-II may be decreased; hepatic lipase may be increased. There is usually no effect on total cholesterol, HDL3 , LDL, or VLDL. 4. Drug Interactions The effectiveness of progestin-only pills is reduced by hepatic enzyme-inducing drugs such as the anticonvulsants phenytoin, carbamazepine, and barbiturates, and the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda antituberculosis drug rifampin. No significant interaction has been found with broad-spectrum antibiotics. 5. Interactions with Laboratory Tests The following endocrine tests may be affected by progestin-only oral contraceptive use: • Sex hormone-binding globulin (SHBG) concentrations may be decreased. • Thyroxine concentrations may be decreased, due to a decrease in thyroid binding globulin (TBG). 6. Carcinogenesis See WARNINGS section. 7. Pregnancy Many studies have found no effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted have not demonstrated significant adverse effects. It is nonetheless prudent to rule out suspected pregnancy before initiating any hormonal contraceptive use. 8. Nursing Mothers In general, no adverse effects have been found on breastfeeding performance or on the health, growth, or development of the infant. However, isolated post-marketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers, resulting in detectable steroid levels in infant plasma. 9. Pediatric Use Safety and efficacy of ORTHO MICRONOR® Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 10. Fertility Following Discontinuation The limited available data indicate a rapid return of normal ovulation and fertility following discontinuation of progestin-only oral contraceptives. 11. Headache The onset or exacerbation of migraine or development of severe headache with focal neurological symptoms which is recurrent or persistent requires discontinuation of progestin-only contraceptives and evaluation of the cause. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INFORMATION FOR THE PATIENT 1. See “Detailed Patient Labeling” for detailed information. 2. Counseling issues The following points should be discussed with prospective users before prescribing progestin-only oral contraceptives: • The necessity of taking pills at the same time every day, including throughout all bleeding episodes. • The need to use a backup method such as condoms and spermicides for the next 48 hours whenever a progestin-only oral contraceptive is taken 3 or more hours late. • The potential side effects of progestin-only oral contraceptives, particularly menstrual irregularities. • The need to inform the healthcare professional of prolonged episodes of bleeding, amenorrhea or severe abdominal pain. • The importance of using a barrier method in addition to progestin-only oral contraceptives if a woman is at risk of contracting or transmitting STDs/HIV. ADVERSE REACTIONS Adverse reactions reported with the use of POPs include: • Menstrual irregularity is the most frequently reported side effect. • Frequent and irregular bleeding are common, while long duration of bleeding episodes and amenorrhea are less likely. • Headache, breast tenderness, nausea, and dizziness are increased among progestin-only oral contraceptive users in some studies. • Androgenic side effects such as acne, hirsutism, and weight gain occur rarely. OVERDOSAGE There have been no reports of serious ill effects from overdosage, including ingestion by children. DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, ORTHO MICRONOR® must be taken exactly as directed. One tablet is taken every day, at the same time. Administration is continuous, with no in terruption between pill packs. See Detailed Patient Labeling for detailed instruction. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED ORTHO MICRONOR® (0.35 mg norethindrone) Tablets are available in a DIALPAK® Tablet Dispenser (NDC 0062-1411-16) containing 28 lime green, round, flat faced, beveled edge tablets, imprinted “ORTHO 0.3 5” on both sides. STORAGE: Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Keep out of reach of children. REFERENCE McCann M, and Potter L. Progestin-Only Oral Contraceptives: A Comprehensive Review. Contraception, 50:60 (Suppl. 1), December 199 4. Truitt ST, Fraser A, Gallo ME, Lopez LM, Grimes DA and Schulz KF. Combined hormonal versus nonhormonal versus progestin-only contraception in lactation (Review). The Cochrane Collaboration. 2007, Issue 3. Halderman, LD and Nelson AL. Impact of early postpartum administration of progestin-only hormonal contraceptives compared with nonhormonal contraceptiv es on short-term breast-feeding patterns. Am J Obstet Gynecol.; 186 (6):1250-1258. Ostrea EM, Mantaring III JB, Silvestre MA. Drugs that affect the fetus and newborn infant via the placenta or breast m ilk. Pediatr Clin N Am; 51(2004): 539-579. Cooke ID, Back DJ, Shroff NE: Norethisterone concentration in breast milk and infant and maternal plasma during ethynodiol diactetate administration. Contraception 1985; 31:611-21. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DETAILED PATIENT LABELING ORTHO MICRONOR® (norethindrone) Tablets This product (like all oral contraceptives) is used to prevent pregnancy. It does not protect against HIV infection (AIDS) or other sexually transmitted diseases. DESCRIPTION ORTHO MICRONOR® Tablets Each tablet contains 0.35 mg norethindrone. Inactive ingredients include corn starch, D&C Green No. 5, D&C Yellow No. 10, lactose, magnesium stearate, and povidone. INTRODUCTION This leaflet is about birth control pills that contain one hormone, a progestin. Please read this leaflet before you begin to take your pills. It is meant to be used along with talking with your healthcare professional. Progestin-only pills are often called “POPs” or “the minipill.” POPs have less progestin than the combined birth control pill (or “the pill”) which contains both an estrogen and a progestin. HOW EFFECTIVE ARE POPs? About 1 in 200 POP users will get pregnant in the first year if they all take POPs perfectly (that is, on time, every day). About 1 in 20 “typical” POP users (including women who are late taking pills or miss pills) gets pregnant in the first year of use. Table 2 will help you compare the efficacy of different methods. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. % of Women Experiencing an % of Women Unintended Pregnancy within the First Year of Use Continuing Use at One Year3 Method Typical Use 1 Perfect Use2 (1) Chance4 (2) 85 (3) 85 (4) Spermicides5 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal6 2 Post-Ovulation 1 Cap7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women Diaphragm7 20 20 9 6 56 56 Withdrawal 19 4 Condom8 Female (Reality®) 21 5 56 Male 14 3 61 Pill 5 71 Progestin Only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera® 0.3 0.3 70 Norplant® and 0.05 0.05 88 Norplant-2® Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Adapted from Hatcher et al, 1998, Ref. # 1. Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9 Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraception.10 Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. 1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. 4 The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 5 Foams, creams, gels, vaginal suppositories, and vaginal film. 6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7 With spermicidal cream or jelly. 8 Without spermicides. 9 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light-orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills). 10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age. ORTHO MICRONOR® Tablets have not been studied for and are not indicated for use in emergency contraception. HOW DO POPs WORK? POPs can prevent pregnancy in different ways including: • They make the cervical mucus at the entrance to the womb (the uterus) too thick for the sperm to get through to the egg. • They prevent ovulation (release of the egg from the ovary) in about half of the cycles. • They also affect other hormones, the fallopian tubes and the lining of the uterus. YOU SHOULD NOT TAKE POPs • If there is any chance you may be pregnant. • If you have breast cancer. • If you have bleeding between your periods that has not been diagnosed. • If you are taking certain drugs for epilepsy (seizures) or for TB. (See “Using POPs with Other Medicines” below.) • If you are hypersensitive, or allergic, to any compone nt of this product. • If you have liver tumors, either b enign or cancerous. • If you have acute liver disease. RISKS OF TAKING POPs Cigarette smoking greatly increases the possibility of suffering heart attacks and strokes. Women who use oral contraceptives are strongly advised not to smoke. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNING: If you have sudden or severe pain in your lower abdomen or stomach area, you may have an ectopic pregnancy or an ovarian cyst. If this happens, you should contact your healthcare professional immediately. Ectopic Pregnancy An ectopic pregnancy is a pregnancy outside the womb. Because POPs protect against pregnancy, the chance of having a pregnancy outside the womb is very low. If you do get pregnant while taking POPs, you have a slightly higher chance that the pregnancy will be ectopic than do users of some other birth control methods. Ovarian Cysts These cysts are small sacs of fluid in the ovary. They are more common among POP users than among users of most other birth control methods. They usually disappear without treatment and rarely cause problems. Cancer of the Reproductive Organs and Breasts Some studies in women who use combined oral contraceptives that contain both estrogen and a progestin have reported an increase in the risk of developing breast cancer, particularly at a younger age and apparently related to duration of use. There is insufficient data to determine whether the use of POPs similarly increases this risk. A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives and there is insufficient data to determine whether the use of POPs increases the risk of developing cancer of the cervix. Liver Tumors In rare cases, combined oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer among women who use combined oral contraceptives. However, liver cancers are rare. There is insufficient data to determine whether POPs increase the risk of liver tumors. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diabetic Women Diabetic women taking POPs do not generally require changes in the amount of insulin they are taking. However, your healthcare professional may monitor you more closely under these conditions. SEXUALLY TRANSMITTED DISEASES (STDs) WARNING: POPs do not protect against getting or giving someone HIV (AIDS) or any other STD, such as chlamydia, gonorrhea, genital warts or herpes. SIDE EFFECTS Irregular Bleeding: The most common side effect of POPs is a change in menstrual bleeding. Your periods may be either early or late, and you may have some spotting between periods. Taking pills late or missing pills can result in some spotting or bleeding. Other Side Effects: Less common side effects include headaches, tender breasts, nausea and dizziness. Weight gain, acne and extra hair on your face and body have been reported, but are rare. If you are concerned about any of these side effects, check with your healthcare professional. USING POPs WITH OTHER MEDICINES Before taking a POP, inform your healthcare professional of any other medication, including over-the-counter medicine, that you may be taking. These medicines can make POPs less effective: Medicines for seizures such as: • Phenytoin (Dilantin®) • Carbamazepine (Tegretol) • Phenobarbital Medicine for TB: • Rifampin (Rifampicin) Before you begin taking any new medicines be sure your healthcare professional knows you are taking a progestin-only birth control pill. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW TO TAKE POPs IMPORTANT POINTS TO REMEMBER • POPs must be taken at the same time every day, so choose a time and then take the pill at that same time every day. Every time you take a pill late, and especially if you miss a pill, you are more likely to get pregnant. • Start the next pack the day after the last pack is finished. There is no break between packs. Always have your next pack of pills ready. • You may have some menstrual spotting between periods. Do not stop taking your pills if this happens. • If you vomit soon after taking a pill, use a backup method (such as a condom and/or a spermicide) for 48 hours. • If you want to stop taking POPs, you can do so at any time, but, if you remain sexually active and don’t wish to become pregnant, be certain to use another birth control method. • If you are not sure about how to take POPs, ask your healthcare professional. STARTING POPs • It’s best to take your first POP on the first day of your menstrual period. • If you decide to take your first POP on another day, use a backup method (such as a condom and/or a spermicide) every time you have sex during the next 48 hours. • If you have had a miscarriage or an abortion, you can start POPs the ne xt day. IF YOU ARE LATE OR MISS TAKING YOUR POPs • If you are more than 3 hours late or you miss one or more POPs: 1) TAKE a missed pill as soon as you remember that you missed it, 2) THEN go back to taking POPs at your regular time, 3) BUT be sure to use a backup method (such as a condom and/or a spermicide) every time you have sex for the next 48 hours. • If you are not sure what to do about the pills you have missed, keep taking POPs and use a backup met hod until you can talk to your healthca re professional. IF YOU ARE BREASTFEEDING • If you are fully breastfeeding (not giving your baby any food or formula), you may start your pills 6 weeks after delivery. • If you are partially breastfeeding (giving your baby some food or formula), you should start taking pills by 3 weeks after delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IF YOU ARE SWITCHING PILLS • If you are switching from the combined pills to POPs, take the first POP the day after you finish the last active combined pill. Do not take any of the 7 inactive pills from the combined pill pack. You should know that many women have irregular periods after switching to POPs, but this is normal and to be expected. • If you are switching from POPs to the combined pills, take the first active combined pill on the first day of your period, even if your POPs pack is not finished. • If you switch to another brand of PO Ps, start the new brand anytime. • If you are breastfeeding, you can switch to another method of birth control at any time, except do not switch to the combined pills until you stop breastfeeding or at least until 6 months after delivery. PREGNANCY WHILE ON THE PILL If you think you are pregnant, contact your healthcare professional. Even though research has shown that POPs do not cause harm to the unborn baby, it is always best not to take any drugs or medicines that you don’t need when you are pregnant. You should get a pregnancy test: • If your period is late and you took one or more pills late or missed taking th em and had sex without a backup method. • Anytime it has been more than 45 days since the beginning of your last period. WILL POPs AFFECT YOUR ABILITY TO GET PREGNANT LATER? If you want to become pregnant, simply stop taking POPs. POPs will not delay your ability to get pregnant. BREASTFEEDING If you are breastfeeding, POPs should not affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported. OVERDOSE No serious problems have been reported when many pills were taken by accident, even by a small child, so there is usually no reason to treat an overdose. OTHER QUESTIONS OR CONCERNS If you have any questions or concerns, check with your healthcare professional. You can also ask for the more detailed “Professional Labeling” written for doctors and other healthcare professionals. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW TO STORE YOUR POPs Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Rx only Keep out of reach of children. Ortho Logo ORTHO-McNEIL PHARMACEUTICAL, INC. Raritan, New Jersey 08869 ©OMP 1998 PRINTED IN U.S.A. REVISED June, 2008 635-50-894- This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:05.549851	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/016954s101lbl.pdf', 'application_number': 16954, 'submission_type': 'SUPPL ', 'submission_number': 101}
10,939	LIMBITROL® company logo (chlordiazepoxide) (amitriptyline HCI) DS (double strength) TABLETS TABLETS Tranquilizer – Antidepressant Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Chlordiazepoxide and Amitriptyline Hydrochloride Tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in the risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. LIMBITROL is not approved for use in pediatric patients. (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use ) DESCRIPTION: LIMBITROL combines for oral administration, chlordiazepoxide, an agent for the relief of anxiety and tension, and amitriptyline, an antidepressant. It is available in DS (double strength) white, film-coated tablets, each containing 10 mg chlordiazepoxide and 25 mg amitriptyline (as the hydrochloride salt); and in blue, film- coated tablets, each containing 5 mg chlordiazepoxide and 12.5 mg amitriptyline (as the hydrochloride salt). Each tablet also contains corn starch, hydroxypropyl cellulose, hyproxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, povidone and propylene glycol; LIMBITROL tablets contain the following colorant system-FD&C Blue No. 1, aluminum lake and titanium dioxide. LIMBITROL DS tablets contain titanium dioxide. Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chlordiazepoxide is a benzodiazepine with the formula 7-chloro-2-(methyl-amino)-5 phenyl-3H-1,4-benzodiazepine 4-oxide. It is a slightly yellow crystalline material and is insoluble in water. The molecular weight is 299.76. Amitriptyline is a dibenzocycloheptadiene derivative. The formula is 10,11-dihydro N,N-dimethyl-5H-dibenzo [a,d] cycloheptene-∆5γ-propylamine hydrochloride. It is a white or practically white crystalline compound that is freely soluble in water. The molecular weight is 313.87. ACTIONS: Both components of LIMBITROL exert their action in the central nervous system. Extensive studies with chlordiazepoxide in many animal species suggest action in the limbic system. Recent evidence indicates that the limbic system is involved in emotional response. Taming action was observed in some species. The mechanism of action of amitriptyline in man is not known, but the drug appears to interfere with the reuptake of norepinephrine into adrenergic nerve endings. This action may prolong the sympathetic activity of biogenic amines. INDICATIONS: LIMBITROL is indicated for the treatment of patients with moderate to severe depression associated with moderate to severe anxiety. The therapeutic response to LIMBITROL occurs earlier and with fewer treatment failures than when either amitriptyline or chlordiazepoxide is used alone. Symptoms likely to respond in the first week of treatment include: insomnia, feelings of guilt or worthlessness, agitation, psychic and somatic anxiety, suicidal ideation and anorexia. CONTRAINDICATIONS: LIMBITROL is contraindicated in patients with hypersensitivity to either benzodiazepines or tricyclic antidepressants. It should not be given concomitantly with a monoamine oxidase inhibitor. Hyperpyretic crises, severe convulsions and deaths have occurred in patients receiving a tricyclic antidepressant and a monoamine oxidase inhibitor simultaneously. When it is desired to replace a monoamine oxidase inhibitor with LIMBITROL, a minimum of 14 days should be allowed to elapse after the former is discontinued. LIMBITROL should then be initiated cautiously with gradual increase in dosage until optimum response is achieved. This drug is contraindicated during the acute recovery phase following myocardial infarction. WARNINGS: Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo- controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but the tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Drug-Related Increases < 18 14 additional cases 18-24 5 additional cases Drug Related Decreases 25-64 1 fewer cases ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All pediatric patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for LIMBITROL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that LIMBITROL is not approved for use in treating bipolar depression. General: Because of the atropine-like action of the amitriptyline component, great care should be used in treating patients with a history of urinary retention or angle-closure glaucoma. In patients with glaucoma, even average doses may precipitate an attack. Severe constipation may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs. Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant drugs, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia and prolongation of conduction time. Myocardial infarction and stroke have been reported in patients receiving drugs of this class. Because of the sedative effects of LIMBITROL, patients should be cautioned about combined effects with alcohol or other CNS depressants. The additive effects may produce a harmful level of sedation and CNS depression. Patients receiving LIMBITROL should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda a motor vehicle. Usage in Pregnancy: Safe use of LIMBITROL during pregnancy and lactation has not been established. Because of the chlordiazepoxide component, please note the following: An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines. (See DRUG ABUSE AND DEPENDENCE section.) PRECAUTIONS: General: Use with caution in patients with a history of seizures. Close supervision is required when LIMBITROL is given to hyperthyroid patients or those on thyroid medication. The usual precautions should be observed when treating patients with impaired renal or hepatic function. Patients with suicidal ideation should not have easy access to large quantities of the drug. The possibility of suicide in depressed patients remains until significant remission occurs. Essential Laboratory Tests: Patients on prolonged treatment should have periodic liver function tests and blood counts. Drug-Drug Interactions Topiramate Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels. Drug and Treatment Interactions: Because of its amitriptyline component, LIMBITROL may block the antihypertensive action of guanethidine or compounds with a similar mechanism of action. Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7% to 10% of caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the type 1c antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. The effects of concomitant administration of LIMBITROL and other psychotropic drugs have not been evaluated. Sedative effects may be additive. Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants and benzodiazepines, thereby delaying elimination and increasing steady-state concentrations of these drugs. Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine (Tagamet). The drug should be discontinued several days before elective surgery. Concurrent administration of ECT and LIMBITROL should be limited to those patients for whom it is essential. Pregnancy: See WARNINGS section. Nursing Mothers: It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug, since many drugs are excreted in human milk. Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Anyone considering the use of Chlordiazepoxide and Amitriptyline Hydrochloride Tablets in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use: In elderly and debilitated patients it is recommended that dosage be limited to the smallest effective amount to preclude the development of ataxia, oversedation, confusion or anticholinergic effects. Of the total number of subjects in clinical studies of LIMBITROL, 74 individuals were 65 years and older. An additional 34 subjects were between 60 and 69 years of age. No Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda overall differences in safety and effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The active ingredients in LIMBITROL are known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of LIMBITROL and observed closely. Clinical studies of LIMBITROL did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with LIMBITROL and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for LIMBITROL. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking LIMBITROL. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. To assure the safe and effective use of benzodiazepines, patients should be informed that, Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug. ADVERSE REACTIONS: Adverse reactions to LIMBITROL are those associated with the use of either component alone. Most frequently reported were drowsiness, dry mouth, constipation, blurred vision, dizziness and bloating. Other side effects occurring less commonly included vivid dreams, impotence, tremor, confusion and nasal congestion. Many symptoms common to the depressive state, such as anorexia, fatigue, weakness, restlessness and lethargy, have been reported as side effects of treatment with both LIMBITROL and amitriptyline. Granulocytopenia, jaundice and hepatic dysfunction of uncertain etiology have also been observed rarely with LIMBITROL. When treatment with LIMBITROL is prolonged, periodic blood counts and liver function tests are advisable. Note: Included in the listing which follows are adverse reactions which have not been reported with LIMBITROL. However, they are included because they have been reported during therapy with one or both of the components or closely related drugs. Cardiovascular: Hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrhythmias, heart block, stroke. Psychiatric: Euphoria, apprehension, poor concentration, delusions, hallucinations, hypomania and increased or decreased libido. Neurologic: Incoordination, ataxia, numbness, tingling and paresthesias of the extremities, extrapyramidal symptoms, syncope, changes in EEG patterns. Anticholinergic: Disturbance of accommodation, paralytic ileus, urinary retention, dilatation of urinary tract. Allergic: Skin rash, urticaria, photosensitization, edema of face and tongue, pruritus. Hematologic: Bone marrow depression including agranulocytosis, eosinophilia, purpura, thrombocytopenia. Gastrointestinal: Nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongue. Endocrine: Testicular swelling and gynecomastia in the male, breast enlargement, galactorrhea and minor menstrual irregularities in the female, elevation and lowering of blood sugar levels, and syndrome of inappropriate ADH (antidiuretic hormone) secretion. Other: Headache, weight gain or loss, increased perspiration, urinary frequency, mydriasis, jaundice, alopecia, parotid swelling. DRUG ABUSE AND DEPENDENCE: Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuance of chlordiazepoxide. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda levels for several months. Withdrawal symptoms (e.g., nausea, headache and malaise) have also been reported in association with abrupt amitriptyline discontinuation. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving chlordiazepoxide or other psychotropic agents because of the predisposition of such patients to habituation and dependence. OVERDOSAGE: Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations: Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia or any of the symptoms listed under ADVERSE REACTIONS. Management: General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination: All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular: A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Serum alkalinization, to a pH of 7.45 to 7.56, using intravenous sodium bicarbonate and hyperventilation (as needed) should be instituted for patients with dysrhythmias and/or QRS widening. A pH > 7.60 or a pCO2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (eg, quinidine, disopyramide and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS: In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management: The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. Poisindex® Toxicologic Management. Topic: Antidepressants, Tricyclic. Micromedex Inc. Vol. 85. Chlordiazepoxide Overdosage: Manifestations of benzodiazepine overdosage include somnolence, confusion, coma and diminished reflexes. Dialysis is of limited value. There have been occasional reports of excitation in patients following benzodiazepine overdosage; if this occurs, barbiturates should not be used. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section). Since LIMBITROL contains amitriptyline, it is important to note that use of the benzodiazepine antagonist flumazenil is contraindicated in patients who are showing signs of serious cyclic antidepressant overdose. DOSAGE AND ADMINISTRATION: Optimum dosage varies with the severity of the symptoms and the response of the individual patient. When a satisfactory response is obtained, dosage should be reduced to the smallest amount needed to maintain the remission. The larger portion of the total daily dose may be taken at bedtime. In some patients, a single dose at bedtime may be sufficient. In general, lower dosages are recommended for elderly patients. LIMBITROL DS (double strength) Tablets are recommended in an initial dosage of 3 or 4 tablets daily in divided doses; this may be increased to 6 tablets daily as required. Some patients respond to smaller doses and can be maintained on 2 tablets daily. LIMBITROL Tablets in an initial dosage of 3 or 4 tablets daily in divided doses may be satisfactory in patients who do not tolerate higher doses. HOW SUPPLIED: LIMBITROL DS (double strength) Tablets are available as white, film- coated, biconvex tablets containing 10 mg chlordiazepoxide and 25 mg amitriptyline (as the hydrochloride salt) in bottles of 100 (NDC 0187-3806-10). Each tablet is engraved “V 3806” on one side. LIMBITROL Tablets are available as blue, film-coated, biconvex tablets containing 5 mg chlordiazepoxide and 12.5 mg amitriptyline (as the hydrochloride salt) in bottles of 100 (NDC 0187-3805-10). Each tablet is engraved “V 3805” on one side. Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Store at 25ºC (77ºF); excursions permitted to 15ºC – 30ºC (59ºF – 86ºF). Store in a dry place. Manufactured for: Heritage Pharmaceuticals Inc. Eatontown, NJ 07724 1.866.901.DRUG (3784) company logo Issued: 04/16 Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • All risks and benefits of treatment with antidepressant medicines • All treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illness, and suicidal thoughts or actions? 1. Antidepressant medications may increase suicidal thoughts or actions in some children, teenagers, and young adults when the medicine is first started. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is first started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • acting aggressive, being angry, or violent • attempts to commit suicide • new or worse depression • acting on dangerous impulses • new or worse anxiety • an extreme increase in activity and talking (mania) • feeling very agitated or restless • panic attacks • other unusual changes in behavior or mood • trouble sleeping (insomnia) • new or worse irritability Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risk of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Reference ID: 3921944 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:05.814856	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016949s039lbl.pdf', 'application_number': 16949, 'submission_type': 'SUPPL ', 'submission_number': 39}
10,942	PMS Black Last Time Saved: 11/24/2009 3:16 PM Document Name: QEN-2316v1.qxp EN-2316 The most commonly encountered acute adverse experiences which demand immediate counter-measures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Patients over 65 years, particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of MARCAINE. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. Central Nervous System Reactions: These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. Cardiovascular System Reactions: High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE.) Allergic: Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. Neurologic: The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control all of which may have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery. OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.) Management of Local Anesthetic Emergencies: The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred. If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory, and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). 4 Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated. Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg to 8 mg/kg and 38 mg/kg to 54 mg/kg respectively. DOSAGE AND ADMINISTRATION The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. The smallest dose and concentration required to produce the desired result should be administered. Dosages of MARCAINE should be reduced for elderly and/or debilitated patients and patients with cardiac and/or liver disease. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible. For specific techniques and procedures, refer to standard textbooks. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. MARCAINE is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION). In recommended doses, MARCAINE produces complete sensory block, but the effect on motor function differs among the three concentrations. 0.25%—when used for caudal, epidural, or peripheral nerve block, produces incomplete motor block. Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently. Onset of action may be slower than with the 0.5% or 0.75% solutions. 0.5%—provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential. 0.75%—produces complete motor block. Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical anesthesia. The duration of anesthesia with MARCAINE is such that for most indications, a single dose is sufficient. Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site. Most experience to date is with single doses of MARCAINE up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization of each case. These doses may be repeated up to once every three hours. In clinical studies to date, total daily doses have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine. The dosages in Table 1 have generally proved satisfactory and are recommended as a guide for use in the average adult. These dosages should be reduced for elderly or debilitated patients. Until further experience is gained, MARCAINE is not recommended for pediatric patients younger than 12 years. MARCAINE is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (Bier Block). Use in Epidural Anesthesia: During epidural administration of MARCAINE, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated. Use only the single-dose ampuls and single-dose vials for caudal or epidural anesthesia; the multiple-dose vials contain a preservative and therefore should not be used for these procedures. Test Dose for Caudal and Lumbar Epidural Blocks: The Test Dose of MARCAINE (0.5% bupivacaine with 1:200,000 epinephrine in a 3 mL ampul) is recommended for use as a test dose when clinical conditions permit prior to caudal and lumbar epidural blocks. This may serve as a warning of unintended intravascular or subarachnoid injection. (See PRECAUTIONS.) The pulse rate and other signs should be monitored carefully immediately following each test dose administration to detect possible intravascular injection, and adequate time for onset of spinal block should be allotted to detect possible intrathecal injection. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or cardiovascular effects from the epinephrine. (See WARNINGS and OVERDOSAGE.) Use in Dentistry: The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time. (See CLINICAL PHARMACOLOGY.) The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% MARCAINE with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, MARCAINE in dentistry is not recommended for pediatric patients younger than 12 years. Unused portions of solution not containing preservatives, i.e., those supplied in single-dose ampuls and single-dose vials, should be discarded following initial use. This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered. Table 1. Recommended Concentrations and Doses of MARCAINE Type of Each Dose Motor Block Conc. (mL) (mg) Block1 Local 0.25%4 up to up to — infiltration max. max. Epidural 0.75%2,4 10-20 75-150 complete 0.5%4 10-20 50-100 moderate to complete 0.25%4 10-20 25-50 partial to moderate Caudal 0.5%4 15-30 75-150 moderate to complete 0.25%4 15-30 37.5-75 moderate Peripheral 0.5%4 5 to 25 to moderate nerves max. max. to complete 0.25%4 5 to 12.5 to moderate max. max. to complete Retrobulbar3 0.75%4 2-4 15-30 complete Sympathetic 0.25% 20-50 50-125 — Dental3 0.5% 1.8-3.6 9-18 — w/epi per site per site Epidural3 0.5% 2-3 10-15 — Test Dose w/epi (10-15 micrograms epinephrine) 1With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% may produce complete motor block. Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery. 2For single-dose use, not for intermittent epidural technique. Not for obstetrical anesthesia. 3See PRECAUTIONS. 4Solutions with or without epinephrine. HOW SUPPLIED These solutions are not for spinal anesthesia. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] MARCAINE —Solutions of MARCAINE that do not contain epinephrine may be autoclaved. Autoclave at 15-pound pressure, 121°C (250°F) for 15 minutes. NDC No. Container Fill Quantity 0.25%—Contains 2.5 mg bupivacaine hydrochloride per mL. 0409-1559-10 Single-dose vials 10 mL box of 10 0409-1559-30 Single-dose vials 30 mL box of 10 0409-1587-50 Multiple-dose vials 50 mL box of 1 0.5%—Contains 5 mg bupivacaine hydrochloride per mL. 0409-1560-10 Single-dose vials 10 mL box of 10 0409-1560-29 Single-dose vials 30 mL box of 10 0409-1610-50 Multiple-dose vials 50 mL box of 1 0.75%—Contains 7.5 mg bupivacaine hydrochloride per mL. 0409-1582-10 Single-dose vials 10 mL box of 10 0409-1582-29 Single-dose vials 30 mL box of 10 MARCAINE with epinephrine 1:200,000 (as bitartrate)—Solutions of MARCAINE that contain epinephrine should not be autoclaved and should be protected from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. NDC No. Container Fill Quantity 0.25% with epinephrine 1:200,000—Contains 2.5 mg bupivacaine hydrochloride per mL. 0409-1746-10 Single-dose vials 10 mL box of 10 0409-1746-30 Single-dose vials 30 mL box of 10 0409-1752-50 Multiple-dose vials 50 mL box of 1 0.5% with epinephrine 1:200,000—Contains 5 mg bupivacaine hydrochloride per mL. 0409-1749-03 Single-dose ampuls 3 mL box of 10 0409-1749-10 Single-dose vials 10 mL box of 10 0409-1749-29 Single-dose vials 30 mL box of 10 0409-1755-50 Multiple-dose vials 50 mL box of 1 Revised: November, 2009 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA Marcaine™ Bupivacaine Hydrochloride Injection, USP Marcaine™ With Epinephrine 1:200,000 (as bitartrate) Bupivacaine Hydrochloride and Epinephrine Injection, USP Rx only DESCRIPTION Bupivacaine hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula: Epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol. It has the following structural formula: MARCAINE is available in sterile isotonic solutions with and without epinephrine (as bitartrate) 1:200,000 for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. Solutions of MARCAINE may be autoclaved if they do not contain epinephrine. Solutions are clear and colorless. Bupivacaine is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. MARCAINE — Sterile isotonic solutions containing sodium chloride. In multiple- dose vials, each mL also contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to between 4 and 6.5 with sodium hydroxide or hydrochloric acid. MARCAINE with epinephrine 1:200,000 (as bitartrate)—Sterile isotonic solutions containing sodium chloride. Each mL contains bupivacaine hydrochloride and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, and 0.1 mg edetate calcium disodium as stabilizer. In multiple-dose vials, each mL also contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to between 3.4 and 4.5 with sodium hydroxide or hydrochloric acid. The specific gravity of MARCAINE 0.5% with epinephrine 1:200,000 (as bitartrate) at 25°C is 1.008 and at 37°C is 1.008. CLINICAL PHARMACOLOGY Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine. Therefore, incremental dosing is necessary. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state. Pharmacokinetics: The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) Structural FormulaStructural Formula This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Approved for FDA Submission L Kindwald 12-03-09 PMS Black Last Time Saved: 11/24/2009 3:16 PM Document Name: QEN-2316v1.qxp usually reduces the rate of absorption and peak plasma concentration of MARCAINE, permitting the use of moderately larger total doses and sometimes prolonging the duration of action. The onset of action with MARCAINE is rapid and anesthesia is long lasting. The duration of anesthesia is significantly longer with MARCAINE than with any other commonly used local anesthetic. It has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesics is reduced. The onset of action following dental injections is usually 2 to 10 minutes and anesthesia may last two or three times longer than lidocaine and mepivacaine for dental use, in many patients up to 7 hours. The duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000. Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug the higher the percentage of drug bound to plasma proteins. Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/ maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. MARCAINE with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Pharmacokinetic studies on the plasma profile of MARCAINE after direct intravenous injection suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized. After injection of MARCAINE for caudal, epidural, or peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours. Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of MARCAINE in adults is 2.7 hours and in neonates 8.1 hours. In clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger patients. Elderly patients also exhibited higher peak plasma concentrations following administration of this product. The total plasma clearance was decreased in these patients. Amide-type local anesthetics such as MARCAINE are metabolized primarily in the liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecoloxylidine is the major metabolite of MARCAINE. The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine. When administered in recommended doses and concentrations, MARCAINE does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia. INDICATIONS AND USAGE MARCAINE is indicated for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Only the 0.25% and 0.5% concentrations are indicated for obstetrical anesthesia. (See WARNINGS.) Experience with nonobstetrical surgical procedures in pregnant patients is not sufficient to recommend use of 0.75% concentration of MARCAINE in these patients. MARCAINE is not recommended for intravenous regional anesthesia (Bier Block). See WARNINGS. The routes of administration and indicated MARCAINE concentrations are: • local infiltration 0.25% • peripheral nerve block 0.25% and 0.5% • retrobulbar block 0.75% • sympathetic block 0.25% • lumbar epidural 0.25%, 0.5%, and 0.75% (0.75% not for obstetrical anesthesia) • caudal 0.25% and 0.5% • epidural test dose 0.5% with epinephrine 1:200,000 • dental blocks 0.5% with epinephrine 1:200,000 (See DOSAGE AND ADMINISTRATION for additional information.) Standard textbooks should be consulted to determine the accepted procedures and techniques for the administration of MARCAINE. CONTRAINDICATIONS MARCAINE is contraindicated in obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. MARCAINE is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type or to other components of MARCAINE solutions. 2 WARNINGS THE 0.75% CONCENTRATION OF MARCAINE IS NOT RECOMMENDED FOR OBSTETRICAL ANESTHESIA. THERE HAVE BEEN REPORTS OF CARDIAC ARREST WITH DIFFICULT RESUSCITATION OR DEATH DURING USE OF MARCAINE FOR EPIDURAL ANESTHESIA IN OBSTETRICAL PATIENTS. IN MOST CASES, THIS HAS FOLLOWED USE OF THE 0.75% CONCENTRATION. RESUSCITATION HAS BEEN DIFFICULT OR IMPOSSIBLE DESPITE APPARENTLY ADEQUATE PREPARATION AND APPROPRIATE MANAGEMENT. CARDIAC ARREST HAS OCCURRED AFTER CONVULSIONS RESULTING FROM SYSTEMIC TOXICITY, PRESUMABLY FOLLOWING UNINTENTIONAL INTRAVASCULAR INJECTION. THE 0.75% CONCENTRATION SHOULD BE RESERVED FOR SURGICAL PROCEDURES WHERE A HIGH DEGREE OF MUSCLE RELAXATION AND PROLONGED EFFECT ARE NECESSARY. LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS, PRECAUTIONS, and OVERDOSAGE.) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH. Local anesthetic solutions containing antimicrobial preservatives, i.e., those supplied in multiple-dose vials, should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentionally or unintentionally, of such preservatives. Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection. MARCAINE with epinephrine 1:200,000 or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of MARCAINE containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamineoxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. Until further experience is gained in pediatric patients younger than 12 years, administration of MARCAINE in this age group is not recommended. Mixing or the prior or intercurrent use of any other local anesthetic with MARCAINE cannot be recommended because of insufficient data on the clinical use of such mixtures. There have been reports of cardiac arrest and death during the use of MARCAINE for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of MARCAINE in this procedure is lacking. Therefore, MARCAINE is not recommended for use in this technique. MARCAINE with epinephrine 1:200,000 contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Single-dose ampuls and single-dose vials of MARCAINE without epinephrine do not contain sodium metabisulfite. PRECAUTIONS General: The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. (See WARNINGS, ADVERSE REACTIONS, and OVERDOSAGE.) During major regional nerve blocks, the patient should have IV fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible. Epidural Anesthesia: During epidural administration of MARCAINE, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. When clinical conditions permit, the test dose should contain epinephrine (10 mcg to 15 mcg has been suggested) to serve as a warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure. The test dose should also contain 10 mg to 15 mg of MARCAINE or an equivalent amount of another local anesthetic to detect an unintended intrathecal administration. This will be evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The Test Dose formulation of MARCAINE contains 15 mg of bupivacaine and 15 mcg of epinephrine in a volume of 3 mL. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects. Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with hypotension or heartblock. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Because amide-local anesthetics such as MARCAINE are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs. Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation anesthetics. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and prompt institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene. (Consult dantrolene sodium intravenous package insert before using.) Use in Head and Neck Area: Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded. (See DOSAGE AND ADMINISTRATION.) Use in Ophthalmic Surgery: Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured (see also WARNINGS and Use In Head and Neck Area, above). As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses. A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local infiltration, including the conjunctiva (see INDICATIONS AND USAGE and PRECAUTIONS, General). Mixing MARCAINE with other local anesthetics is not recommended because of insufficient data on the clinical use of such mixtures. When MARCAINE 0.75% is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone should determine readiness of the patient for surgery. 3 Use in Dentistry: Because of the long duration of anesthesia, when MARCAINE 0.5% with epinephrine is used for dental injections, patients should be cautioned about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advised not to chew solid foods or test the anesthetized area by biting or probing. Information for Patients: When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the package insert of MARCAINE. Patients receiving dental injections of MARCAINE should be cautioned not to chew solid foods or test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours). Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals of most local anesthetics including bupivacaine to evaluate the carcinogenic potential have not been conducted. Mutagenic potential or the effect on fertility has not been determined. There is no evidence from human data that MARCAINE may be carcinogenic or mutagenic or that it impairs fertility. Pregnancy Category C: Decreased pup survival in rats and an embryocidal effect in rabbits have been observed when bupivacaine hydrochloride was administered to these species in doses comparable to nine and five times respectively the maximum recommended daily human dose (400 mg). There are no adequate and well-controlled studies in pregnant women of the effect of bupivacaine on the developing fetus. Bupivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. This does not exclude the use of MARCAINE at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.) Labor and Delivery: SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75% MARCAINE. MARCAINE is contraindicated for obstetrical paracervical block anesthesia. Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine. It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left. Nursing Mothers: Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue nursing or not administer bupivacaine, taking into account the importance of the drug to the mother. Pediatric Use: Until further experience is gained in pediatric patients younger than 12 years, administration of MARCAINE in this age group is not recommended. Continuous infusions of bupivacaine in children have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE.) Geriatric Use: Patients over 65 years, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with MARCAINE. (See ADVERSE REACTIONS.) Elderly patients may require lower doses of MARCAINE. (See PRECAUTIONS, Epidural Anesthesia and DOSAGE AND ADMINISTRATION.) In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. (See CLINICAL PHARMACOLOGY.) This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY.) ADVERSE REACTIONS Reactions to MARCAINE are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:05.818025	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/016964s069lbl.pdf', 'application_number': 16964, 'submission_type': 'SUPPL ', 'submission_number': 69}
10,941	Drawing #: DD301300 Style: N9 Dimensions: 7-5/8” x 3” x 2-13/16” x 2-31/32” x 3-1/4” CA-XXXX (XX/XX) 0 9 8 7 6 5 4 3 2 1 2. 1/16 INCH QUIET ZONE REQUIRED ON ALL SIDES OF COMMODITY NUMBER. COMMODITY NUMBERS TO BE 8 POINT FUTURA REGULAR. 3. UNVARNISHED AND COPY FREE LOCATION FOR PRINTING LOT, EXP. AND MFG. DATE, ETC. IN THE PLANT. AREAS MUST BE A MINIMUM OF 1-1/2 X 1/2 INCH. 4. LOCATION FOR PRINTING BAR CODE (WHEN PRESENT ON ARTWORK). WHEN SPACE ALLOWS, BAR CODE TO: INCLUDE 1/4 QUIET ZONE ON EACH END. USE 10 MIL NARROW BAR WIDTH AND 0.4 INCH HEIGHT. 6. AREA FOR TAMPER EVIDENT TAPE/LABEL, IF SPECIFIED ON M.P.S. ARE TO BE UNVARNISHED AND COPY FREE. AREA MAY BE USED FOR COPY WHEN TAMPER EVIDENT TAPE/LABEL IS NOT SPECIFIED. 7. LOCATION FOR COMMODITY BAR CODE. APPROXIMATELY CENTERED ON MINOR FLAP. ENCODE THE SIX (6) DIGIT COMMODITY NUMBER (WITHOUT THE HYPHEN). INCLUDE 1/4 INCH QUIET ZONE ON EACH END, USE 10 MIL NARROW BAR WIDTH AND 0.4 INCH HEIGHT. See Note 6 ---> Copy Direction ---> See Note 3 See Note 4 ---> See Note 6 ---> Copy Direction ---> Copy Direction ---> See Note 7 ---> Contains epinephrine – do not autoclave. Discard unused portion after initial use. Each mL contains 5 mg bupivacaine HCl and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, 0.1 mg edetate calcium disodium as stabilizer, and NaCl to make isotonic, in Water for Injection. pH adjusted with NaOH or HCl. Usual dosage: See package insert. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] with epinephrine 1:200,000 (as bitartrate) (01) 1 030409 174929 7 TEST 6 (10/05) ----------------------------- ---- ------- ------------------------------------------ ---- ------ ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ---------- -------- ----- ---------- ---------- ©Hospira 2005 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA NDC 0409-1749-29 M-643 CA0672 --------------------------------------- ---------------------------------------------- --------------- ------------------------------ -------------------------------------------- ------------------ ---------------------------------------- --------------------------- Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) only 30 mL (150 mg) 10 Single Dose Vials PRESERVATIVE-FREE 30 mL (150 mg) NDC 0409-1749-29 PRESERVATIVE-FREE M-643 Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) 30 mL (150 mg) NDC 0409-1749-29 PRESERVATIVE-FREE M-643 Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites NDC 0409-1749-29 M-643 Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) only 30 mL (150 mg) 10 Single Dose Vials PRESERVATIVE-FREE (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) Drawing #: DD301300 Style: N7 Dimensions: 5-5/8” x 2-1/4” x 2-3/16” x 2-7/32” x 3-1/4” 0 9 8 7 6 5 4 3 2 1 CA-XXXX (XX/XX) 2. 1/16 INCH QUIET ZONE REQUIRED ON ALL SIDES OF COMMODITY NUMBER. COMMODITY NUMBERS TO BE 8 POINT FUTURA REGULAR. 3. UNVARNISHED AND COPY FREE LOCATION FOR PRINTING LOT, EXP. AND MFG. DATE, ETC. IN THE PLANT. AREAS MUST BE A MINIMUM OF 1-1/2 X 1/2 INCH. 4. LOCATION FOR PRINTING BAR CODE (WHEN PRESENT ON ARTWORK). WHEN SPACE ALLOWS, BAR CODE TO: INCLUDE 1/4 QUIET ZONE ON EACH END. USE 10 MIL NARROW BAR WIDTH AND 0.4 INCH HEIGHT. 6. AREA FOR TAMPER EVIDENT TAPE/LABEL, IF SPECIFIED ON M.P.S. ARE TO BE UNVARNISHED AND COPY FREE. AREA MAY BE USED FOR COPY WHEN TAMPER EVIDENT TAPE/LABEL IS NOT SPECIFIED. 7. LOCATION FOR COMMODITY BAR CODE. APPROXIMATELY CENTERED ON MINOR FLAP. ENCODE THE SIX (6) DIGIT COMMODITY NUMBER (WITHOUT THE HYPHEN). INCLUDE 1/4 INCH QUIET ZONE ON EACH END, USE 10 MIL NARROW BAR WIDTH AND 0.4 INCH HEIGHT. See Note 7 ---> Copy Direction ---> See Note 6 ---> Copy Direction ---> See Note 3 See Note 4 ---> See Note 6 ---> Copy Direction ---> Contains epinephrine – do not autoclave. Discard unused portion after initial use. Each mL contains 2.5 mg bupivacaine HCl and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, 0.1 mg edetate calcium disodium as stabilizer, and NaCl to make isotonic, in Water for Injection. pH adjusted with NaOH or HCl. Usual dosage: See insert. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] ©Hospira 2005 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA (01) 1 030409 174610 4 TEST 1 (10/05) ----------------------------- ---- ------- ------------------------------------------ ---- ------ ------ ------------- ------------------------------------ --------------- ----- ----------------------------- ----------------------- ----------------------- ---------- -------- ----- ---------------------- ---------- CA0803 --------------------------------- ------------------------ -------------------------- --------------- ------------------------------ ------------------------------- -------------------------------- ------------------------- --------------------------- -------------- 10 mL (25 mg) 10 Single Dose Vials NDC 0409-1746-10 PRESERVATIVE-FREE M-632 Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION, NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) only 10 mL (25 mg) NDC 0409-1746-10 M-632 Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION, NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) PRESERVATIVE-FREE 10 mL (25 mg) NDC 0409-1746-10 M-632 Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION, NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) PRESERVATIVE-FREE 10 mL (25 mg) 10 Single Dose Vials NDC 0409-1746-10 PRESERVATIVE-FREE M-632 Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION, NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) only (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) Drawing #: DD301300 Style: N9 Dimensions: 7-5/8” x 3” x 2-13/16” x 2-31/32” x 3-1/4” CA-XXXX (XX/XX) 0 9 8 7 6 5 4 3 2 1 2. 1/16 INCH QUIET ZONE REQUIRED ON ALL SIDES OF COMMODITY NUMBER. COMMODITY NUMBERS TO BE 8 POINT FUTURA REGULAR. 3. UNVARNISHED AND COPY FREE LOCATION FOR PRINTING LOT, EXP. AND MFG. DATE, ETC. IN THE PLANT. AREAS MUST BE A MINIMUM OF 1-1/2 X 1/2 INCH. 4. LOCATION FOR PRINTING BAR CODE (WHEN PRESENT ON ARTWORK). WHEN SPACE ALLOWS, BAR CODE TO: INCLUDE 1/4 QUIET ZONE ON EACH END. USE 10 MIL NARROW BAR WIDTH AND 0.4 INCH HEIGHT. 6. AREA FOR TAMPER EVIDENT TAPE/LABEL, IF SPECIFIED ON M.P.S. ARE TO BE UNVARNISHED AND COPY FREE. AREA MAY BE USED FOR COPY WHEN TAMPER EVIDENT TAPE/LABEL IS NOT SPECIFIED. 7. LOCATION FOR COMMODITY BAR CODE. APPROXIMATELY CENTERED ON MINOR FLAP. ENCODE THE SIX (6) DIGIT COMMODITY NUMBER (WITHOUT THE HYPHEN). INCLUDE 1/4 INCH QUIET ZONE ON EACH END, USE 10 MIL NARROW BAR WIDTH AND 0.4 INCH HEIGHT. See Note 6 ---> Copy Direction ---> See Note 3 See Note 4 ---> See Note 6 ---> Copy Direction ---> Copy Direction ---> See Note 7 ---> Contains epinephrine – do not autoclave. Discard unused portion after initial use. Each mL contains 2.5 mg bupivacaine HCl and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, 0.1 mg edetate calcium disodium as stabilizer, and NaCl to make isotonic, in Water for Injection. pH adjusted with NaOH or HCl. Usual dosage: See package insert. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] ©Hospira 2005 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA (01) 1 030409 174630 2 TEST 2 (10/05) ----------------------------- ---- ------- ------------------------------------------ ---- ------ ------ ------------- ------------------------------------ --------------- ----- -------- --------------------- ------------------------ ----------------------- ---------- -------- ----- ---------------------- ---------- CA0804 M-633 --------------------------------- ------------------------- -------------------------- --------------- ------------------------------ ------------------------------- -------------------------------- ------------------------- --------------------------- -------------- 30 mL (75 mg) 10 Single Dose Vials NDC 0409-1746-30 PRESERVATIVE-FREE Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION, NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites only with epinephrine 1:200,000 (as bitartrate) Marcaine ®0.25% bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION, NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites only with epinephrine 1:200,000 (as bitartrate) Marcaine ®0.25% bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION, NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites only with epinephrine 1:200,000 (as bitartrate) M-633 30 mL (75 mg) 10 Single Dose Vials NDC 0409-1746-30 PRESERVATIVE-FREE Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION, NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites only with epinephrine 1:200,000 (as bitartrate) 30 mL (75 mg) NDC 0409-1746-30 PRESERVATIVE-FREE M-633 30 mL (75 mg) NDC 0409-1746-30 PRESERVATIVE-FREE M-633 (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) Drawing #: DD301300 Style: N7 Dimensions: 5-5/8” x 2-1/4” x 2-3/16” x 2-7/32” x 3-1/4” 0 9 8 7 6 5 4 3 2 1 CA-XXXX (XX/XX) 2. 1/16 INCH QUIET ZONE REQUIRED ON ALL SIDES OF COMMODITY NUMBER. COMMODITY NUMBERS TO BE 8 POINT FUTURA REGULAR. 3. UNVARNISHED AND COPY FREE LOCATION FOR PRINTING LOT, EXP. AND MFG. DATE, ETC. IN THE PLANT. AREAS MUST BE A MINIMUM OF 1-1/2 X 1/2 INCH. 4. LOCATION FOR PRINTING BAR CODE (WHEN PRESENT ON ARTWORK). WHEN SPACE ALLOWS, BAR CODE TO: INCLUDE 1/4 QUIET ZONE ON EACH END. USE 10 MIL NARROW BAR WIDTH AND 0.4 INCH HEIGHT. 6. AREA FOR TAMPER EVIDENT TAPE/LABEL, IF SPECIFIED ON M.P.S. ARE TO BE UNVARNISHED AND COPY FREE. AREA MAY BE USED FOR COPY WHEN TAMPER EVIDENT TAPE/LABEL IS NOT SPECIFIED. 7. LOCATION FOR COMMODITY BAR CODE. APPROXIMATELY CENTERED ON MINOR FLAP. ENCODE THE SIX (6) DIGIT COMMODITY NUMBER (WITHOUT THE HYPHEN). INCLUDE 1/4 INCH QUIET ZONE ON EACH END, USE 10 MIL NARROW BAR WIDTH AND 0.4 INCH HEIGHT. See Note 7 ---> Copy Direction ---> See Note 6 ---> Copy Direction ---> See Note 3 See Note 4 ---> See Note 6 ---> Copy Direction ---> with epinephrine 1:200,000 (as bitartrate) (01) 1 030409 174910 5 TEST 5 (10/05) NDC 0409-1749-10 M-642 Contains epinephrine – do not autoclave. Discard unused portion after initial use. Each mL contains 5 mg bupivacaine HCl and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, 0.1 mg edetate calcium disodium as stabilizer, and NaCl to make isotonic, in Water for Injection. pH adjusted with NaOH or HCl. Usual dosage: See package insert. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] ----------------------------- ---- ------- ------------------------------------------ ---- ------ ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- --------------------- ----------------------- ---------- -------- ----- ---------- ---------- ©Hospira 2005 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA CA0671 ------------------------------------------------- ------------------------------------ --------------- ------------------------------ ------------------------------- -------------------------------- ------------------------- ----------------------------------------- 10 mL (50 mg) 10 Single Dose Vials PRESERVATIVE-FREE Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites only with epinephrine 1:200,000 (as bitartrate) NDC 0409-1749-10 M-642 10 mL (50 mg) 10 Single Dose Vials PRESERVATIVE-FREE Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites only 10 mL (50 mg) NDC 0409-1749-10 PRESERVATIVE-FREE M-642 Marcaine® 0.5% bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites 10 mL (50 mg) NDC 0409-1749-10 PRESERVATIVE-FREE M-642 with epinephrine 1:200,000 (as bitartrate) Marcaine® 0.5% bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK, CAUDAL, and EPIDURAL ANESTHESIA Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) TEST 11 (10/05) (01) 0 030409 175250 4 only 50 mL Multiple-Dose Vial Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP with epinephrine 1:200,000 (as bitartrate) Each mL contains 2.5 mg bupivacaine HCl and 0.0091 mg epinephrine bitartrate, with 1 mg methylparaben as preservative, 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, 0.1 mg edetate calcium disodium as stabilizer, and NaCl to make isotonic, in Water for Injection. pH adjusted with NaOH or HCl. ©Hospira 2005 Printed in USA Hospira, Inc. Lake Forest, IL 60045 USA NDC 0409-1752-50 M-635 NDC 0409-1752-50 M-635 50 mL Multiple-Dose Vial Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION and NERVE BLOCK Not for caudal, epidural, or spinal anesthesia Contains epinephrine– do not autoclave Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) 50 mL Multiple-Dose Vial Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP Dosage: See package insert. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] NDC 0409-1752-50 M-635 with epinephrine 1:200,000 (as bitartrate) ------ ------------- ------------------------------------ --------------- ----- -------- --------------------- ----------------------- ----------------------- ---------- ------------- --------------- ---- ------------- --- ------- ----- ------ --------- ----- ----------------------- ---------- 50 mL Multiple-Dose Vial Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP with epinephrine 1:200,000 (as bitartrate) NDC 0409-1752-50 M-635 50 mL Multiple-Dose Vial Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP with epinephrine 1:200,000 (as bitartrate) (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) ------------- - ------------ --------- - - ------------- ----- ------- NDC 0409-1755-50 M-645 50 mL Multiple-Dose Vial Marcaine ® 0.5% with epinephrine 1:200,000 (as bitartrate) bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK NDC 0409-1755-50 M-645 50 mL Multiple-Dose Vial Marcaine ® 0.5% with epinephrine 1:200,000 (as bitartrate) bupivacaine hydrochloride and epinephrine injection, USP NDC 0409-1755-50 M-645 50 mL Multiple-Dose Vial Marcaine ® 0.5% with epinephrine 1:200,000 (as bitartrate) bupivacaine hydrochloride and epinephrine injection, USP NDC 0409-1755-50 M-645 50 mL Multiple-Dose Vial Marcaine ®0.5% with epinephrine 1:200,000 (as bitartrate) bupivacaine hydrochloride and epinephrine injection, USP NDC 0409-1755-50 M-645 50 mL Multiple-Dose Vial Marcaine ® 0.5% with epinephrine 1:200,000 (as bitartrate) bupivacaine hydrochloride and epinephrine injection, USP (01) 0 030409 175550 5 ©Hospira 2005 Printed in USA Hospira, Inc. Lake Forest, IL 60045 USA TEST 13 (10/05) Each mL contains 5 mg bupivacaine HCl and 0.0091 mg epinephrine bitartrate, with 1 mg methylparaben as preservative, 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, 0.1 mg edetate calcium disodium as stabilizer, and NaCl to make isotonic, in Water for Injection. pH adjusted with NaOH or HCl. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Usual dosage: see package insert. ------------------------------------ --------------- ----- -------- --------------------- ----------------------- ----------------------- ------------- --------------- ---- ------------- --- ------- ----- ------ --------- ----- -------------- Not for caudal, epidural, or spinal anesthesia Contains epinephrine– do not autoclave Warning: Contains Sulfites only (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) Hospira, Inc., Lake Forest, IL 60045 USA TEST 14 (10/04) Each mL contains 5 mg bupivacaine HCl, and 0.0091 mg epinephrine bitartrate, with 1 mg methylparaben as preservative, 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, 2 mg ascorbic acid, 0.0017 mL 60% sodium lactate, 0.1 mg edetate calcium disodium, and NaCl to make isotonic. pH adjusted with NaOH or HCl. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Usual dosage: See package insert. ©Hospira 2005 Printed in USA ------ ------------- ------------------------------------ --------------- ----- -------- --------------------- ----------------------- ----------------------- ----- --- ------------- --------------- ---- ------------- --- ------- ----- ------ --------- ----- ---------- -------------- 50 mL Multiple-Dose Vial NDC 0409-1755-50 Marcaine ® 0.5% M-645 with epinephrine 1:200,000 (as bitartrate) bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK Not for caudal, epidural, or spinal anesthesia Contains epinephrine–do not autoclave Warning: Contains Sulfites only (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) 50 mL Multiple-Dose Vial Marcaine ® 0.25% ©Hospira 2005 Printed in USA with epinephrine 1:200,000 (as bitartrate) bupivacaine hydrochloride and epinephrine injection, USP for INFILTRATION and NERVE BLOCK Not for caudal, epidural, or spinal anesthesia Contains epinephrine–do not autoclave Warning: Contains Sulfites Each mL contains 2.5 mg bupivacaine HCl, and 0.0091 mg epinephrine bitartrate, with 1 mg methylparaben as preservative, 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, 2 mg ascorbic acid, 0.0017 mL 60% sodium lactate, 0.1 mg edetate calcium disodium, and NaCl to make isotonic, in Water for Injection. pH adjusted with NaOH or HCl. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Dosage: See package insert. only TEST 12 (11/05) Hospira, Inc., Lake Forest, IL 60045 USA ----------------------------- ---- ------- ------------------------------------------ ---- ------ ------ ------------- ------------------------------------ --------------- ----- -------- --------------------- ----------------------- ----------------------- ---------- --------- ----- ---------------------- ---------- NDC 0409-1752-50 M635 (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) Each mL contains 5 mg bupivacaine HCI and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, 2 mg ascorbic acid, 0.0017 mL 60% sodium lactate, 0.1 mg edetate calcium disodium, and NaCI to make isotonic. pH adjusted with NaOH or HCI. Usual dosage: See package insert. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Contains epinephrine – do not autoclave Discard unused portion after initial use ©Hospira 2005 Printed in USA Hospira, Inc. Lake Forest, IL 60045 USA Marcaine ® 0.5% (01) 0 030409 174929 0 with epinephrine 1:200,000 (as bitartrate) TEST 10 (10/05) ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ---------- ------------- --------------- ---- ------------- --- ------- ----- ------ --------- ----- ---------- ---------- bupivacaine hydrochloride and epinephrine injection, USP for Nerve Block, Caudal, and Epidural anesthesia Not for spinal anesthesia Warning: Contains Sulfites 30 mL (150 mg) NDC 0409-1749-29 Single Dose Vial M-643 PRESERVATIVE-FREE only (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) Each mL contains 5 mg bupivacaine HCl and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, 2 mg ascorbic acid, 0.0017 mL 60% sodium lactate, 0.1 mg edetate calcium disodium, and NaCl to make isotonic. pH adjusted with NaOH or HCl. Usual dosage: See package insert. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Discard unused portion after initial use. ©Hospira 2005 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA PRESERVATIVE-FREE Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP for NERVE BLOCK, CAUDAL, and EPIDURAL anesthesia Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) Contains epinephrine — do not autoclave only TEST 9 (10/05) ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ---------- ------------- --------------- ---- ------------- --- ------- ----- ------ -------- ----- ---------- ---------- 10 mL (50 mg) Single Dose Vial NDC 0409-1749-10 M-642 (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) TEST 3 (10/05) Each mL contains 2.5 mg bupivacaine HCl and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, 2 mg ascorbic acid, 0.0017 mL 60% sodium lactate, 0.1 mg edetate calcium disodium, and NaCl to make isotonic. pH adjusted with NaOH or HCl. Usual dosage: See insert. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Contains epinephrine–do not autoclave. Discard unused portion after initial use. ©Hospira 2005 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA ----------------------------- ---- ------- ------------------------------------------ ---- ------ ------ ------------- ------------------------------------ --------------- ----- -------- --------------------- ----------------------- ----------------------- ---------- -------- ----- ---------------------- ---------- 10 mL (25 mg) Single Dose Vial NDC 0409-1746-10 PRESERVATIVE-FREE Marcaine® 0.25% bupivacaine hydrochloride and epinephrine injection, USP for Infiltration, Nerve Block, Caudal, and Epidural anesthesia. Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) only (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) Each mL contains 2.5 mg bupivacaine HCl, and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, 2 mg ascorbic acid, 0.0017 mL 60% sodium lactate, 0.1 mg edetate calcium disodium, and NaCl to make isotonic. pH adjusted with NaOH or HCl. Usual dosage: See package insert. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Contains epinephrine-do not autoclave. Discard unused portion after initial use. ©Hospira 2005 Printed in USA Hospira, Inc. Lake Forest, IL 60045 USA 30 mL (75 mg) Single Dose Vial NDC 0409-1746-30 PRESERVATIVE-FREE M-633 Marcaine ® 0.25% bupivacaine hydrochloride and epinephrine injection, USP for Infiltration, Nerve Block, Caudal, and Epidural anesthesia Not for spinal anesthesia Warning: Contains Sulfites with epinephrine 1:200,000 (as bitartrate) ----------------------------- ---- ------- ------------------------------------------ ---- ------ ------ ------------- ------------------------------------ --------------- ----- ----------------------------- ----------------------- ----------------------- ---------- -------- ----- ---------------------- ---------- TEST 4 (10/05) only (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) Marcaine® 0.5% with epinephrine 1:200,000 (as bitartrate) TEST 7 (10/05) only Exp. Lot ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ---------- ------------- --------------- ---- ------------- --- ------- ----- ------ -------- ----- ---------- ------- ---------- bupivacaine hydrochloride and epinephrine injection, USP Test Dose Contains epinephrine–do not autoclave Warning: Contains Sulfites for use Prior to EPIDURAL and CAUDAL ANESTHESIA Not for spinal anesthesia Hospira, Inc., Lake Forest, IL 60045 USA 3 mL (15 mg) NDC 0409-1749-03 PRESERVATIVE-FREE (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4) 3 mL (15 mg) 10 Ampuls NDC 0409-1749-03 PRESERVATIVE-FREE Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP Test Dose for use Prior to EPIDURAL and CAUDAL ANESTHESIA Not for spinal anesthesia Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Contains epinephrine – do not autoclave. Warning: Contains Sulfites These ampuls bear a color band signifying that they are Easy Break Ampuls. The tops snap off at the constriction, regardless of the position of the color band. Each mL contains 5 mg bupivacaine HCl and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate, 0.1 mg edetate calcium disodium, and NaCl to make isotonic. pH adjusted with NaOH or HCl. No preservative added. Protect from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. Discard unused portion after initial use. Usual dosage: See package insert. ©Hospira 2005 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA with epinephrine 1:200,000 (as bitartrate) M-640 ------ ------------- ----------------------------------- --------------- ----- -------- --------------------- ---------------------- ----------------------- ---------- ------------- --------------- ---- ------------- --- ------- ----- ------ -------- ----- ---------- ---------- (01) 1 030409 174903 7 TEST 8 (10/05) only 3 mL (15 mg) 10 Ampuls NDC 0409-1749-03 PRESERVATIVE-FREE Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP Test Dose with epinephrine 1:200,000 (as bitartrate) 3 mL (15 mg) 10 Ampuls NDC 0409-1749-03 PRESERVATIVE-FREE Marcaine ® 0.5% bupivacaine hydrochloride and epinephrine injection, USP Test Dose with epinephrine 1:200,000 (as bitartrate) (b)(4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (b)(4) (b)(4)	custom-source	2025-02-12T13:44:05.819427	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/016964s061lbl.pdf', 'application_number': 16964, 'submission_type': 'SUPPL ', 'submission_number': 61}
10,946	Patient Information FLUOROPLEX® (FLOOR-oh-plex) (fluorouracil) 1% Topical Cream Important: FLUOROPLEX Cream is for use on skin only (topical). Apply with care near the eyes, nose and mouth. What is FLUOROPLEX Cream? FLUOROPLEX Cream is a prescription medicine used on the skin to treat multiple actinic (solar) keratosis. It is not known if FLUOROPLEX Cream is safe and effective in children. Who should not use FLUOROPLEX Cream? Do not use FLUOROPLEX Cream if: • you are pregnant or may become pregnant. FLUOROPLEX Cream may harm your unborn baby. Stop using FLUOROPLEX Cream and tell your healthcare provider right away if you become pregnant while using FLUOROPLEX Cream. • you are allergic to any of the ingredients in FLUOROPLEX Cream. See the end of this leaflet for a list of ingredients in FLUOROPLEX Cream. Before using FLUOROPLEX Cream, tell your healthcare provider about all of your medical conditions, including if you: • are breastfeeding or plan to breastfeed. It is not known if FLUOROPLEX Cream passes into your breast milk. You should not breastfeed during treatment with FLUOROPLEX Cream. How should I use FLUOROPLEX® Topical Cream? • Use FLUOROPLEX Cream exactly as your healthcare provider tells you. Your healthcare provider will tell you where to apply FLUOROPLEX Cream, how often and how long to apply it. • FLUOROPLEX Cream is usually applied 2 times a day for 2 to 6 weeks. • Use your fingertips to apply enough FLUOROPLEX Cream to cover the areas to be treated on your face or other affected areas, as instructed by your healthcare provider. • Skin reactions are expected when you use FLUOROPLEX Cream. These skin reactions begin with redness, usually followed by dryness or tenderness and crusting of your skin. Before you see any healing of your skin, these skin reactions continue to progress. Stop using FLUOROPLEX Cream when you see raw areas (erosion and ulcers) and shedding of dead skin (sloughing). Be sure to follow your healthcare provider’s instructions about when to stop using FLUOROPLEX Cream. • If your skin reaction bothers you or is severe, or if you are not sure what to do, call your healthcare provider for instructions. • Avoid letting FLUOROPLEX Cream build up in the skin folds around your eyes, nose or mouth. • Wash your hands right away after you apply FLUOROPLEX Cream. If you accidentally get FLUOROPLEX Cream in your eyes, flush your eyes with water or normal saline. What should I avoid while using FLUOROPLEX Cream? • Avoid covering the treated areas with an airtight dressing, unless your healthcare provider tells you to. • Avoid sunlight and ultraviolet lights, such as sun lamps and tanning machines. FLUOROPLEX Cream can make your skin sensitive to light. You could get a severe sunburn. What are the possible side effects of FLUOROPLEX Cream? • Skin reactions including possible allergic reactions (allergic contact dermatitis). You may get skin reactions such as: o pain o irritation o darkening of the skin o itching o redness and swelling o scarring o burning o small blood vessels that can be seen under the skin Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of FLUOROPLEX Cream. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store FLUOROPLEX Cream? • Do not freeze FLUOROPLEX Cream. • Store FLUOROPLEX Cream between 59°F to 86°F (15°C to 30°C) in tight containers. Keep FLUOROPLEX Cream and all medicines out of the reach of children. General Information about the safe and effective use of FLUOROPLEX Cream. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use FLUOROPLEX Cream for a condition for which it was not prescribed. Do not give FLUOROPLEX Cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about FLUOROPLEX Cream that is written for the health professionals. Reference ID: 3963426 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What are the ingredients in FLUOROPLEX Cream? Active ingredient: fluorouracil Inactive ingredients: benzyl alcohol, emulsifying wax, isopropyl myristate, mineral oil, purified water, and sodium hydroxide Manufactured by: Aqua Pharmaceuticals, an Almirall Company, Exton, PA 19341 U.S.A. ® Marks owned by Aqua Pharmaceuticals Made in Germany For more information, call 1-866-665-2782. This Patient Information has been approved by the U.S. Food and Drug Administration Issued: July 2016 Reference ID: 3963426 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:06.208193	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016988s030lbl.pdf', 'application_number': 16988, 'submission_type': 'SUPPL ', 'submission_number': 30}
10,943	MarcaineTM Bupivacaine Hydrochloride Injection, USP MarcaineTM With Epinephrine 1:200,000 (as bitartrate) Bupivacaine Hydrochloride and Epinephrine Injection, USP Rx only DESCRIPTION Bupivacaine hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula: structural formula Epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol. It has the following structural formula: structural formula MARCAINE is available in sterile isotonic solutions with and without epinephrine (as bitartrate) 1:200,000 for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. Solutions of MARCAINE may be autoclaved if they do not contain epinephrine. Solutions are clear and colorless. Bupivacaine is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. MARCAINE — Sterile isotonic solutions containing sodium chloride. In multiple-dose vials, each mL also contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to between 4 and 6.5 with sodium hydroxide or hydrochloric acid. MARCAINE with epinephrine 1:200,000 (as bitartrate)—Sterile isotonic solutions containing sodium chloride. Each mL contains bupivacaine hydrochloride and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, and 0.1 mg edetate calcium disodium as stabilizer. In multiple-dose vials, each mL also contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to between 3.4 and 4.5 with sodium hydroxide or hydrochloric acid. The specific gravity of MARCAINE 0.5% with epinephrine 1:200,000 (as bitartrate) at 25°C is 1.008 and at 37°C is 1.008. CLINICAL PHARMACOLOGY Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and wEN-2916v03 Page 1 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine. Therefore, incremental dosing is necessary. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state. Pharmacokinetics: The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma concentration of MARCAINE, permitting the use of moderately larger total doses and sometimes prolonging the duration of action. The onset of action with MARCAINE is rapid and anesthesia is long lasting. The duration of anesthesia is significantly longer with MARCAINE than with any other commonly used local anesthetic. It has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesics is reduced. The onset of action following dental injections is usually 2 to 10 minutes and anesthesia may last two or three times longer than lidocaine and mepivacaine for dental use, in many patients up to 7 hours. The duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000. Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug the higher the percentage of drug bound to plasma proteins. Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/ maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. MARCAINE with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Pharmacokinetic studies on the plasma profile of MARCAINE after direct intravenous injection suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the wEN-2916v03 Page 2 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized. After injection of MARCAINE for caudal, epidural, or peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours. Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of MARCAINE in adults is 2.7 hours and in neonates 8.1 hours. In clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger patients. Elderly patients also exhibited higher peak plasma concentrations following administration of this product. The total plasma clearance was decreased in these patients. Amide-type local anesthetics such as MARCAINE are metabolized primarily in the liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecoloxylidine is the major metabolite of MARCAINE. The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine. When administered in recommended doses and concentrations, MARCAINE does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia. INDICATIONS AND USAGE MARCAINE is indicated for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Only the 0.25% and 0.5% concentrations are indicated for obstetrical anesthesia. (See WARNINGS.) Experience with nonobstetrical surgical procedures in pregnant patients is not sufficient to recommend use of 0.75% concentration of MARCAINE in these patients. MARCAINE is not recommended for intravenous regional anesthesia (Bier Block). See WARNINGS. The routes of administration and indicated MARCAINE concentrations are: ∙ local infiltration 0.25% ∙ peripheral nerve block 0.25% and 0.5% ∙ retrobulbar block 0.75% ∙ sympathetic block 0.25% ∙ lumbar epidural 0.25%, 0.5%, and 0.75% (0.75% not for obstetrical anesthesia) ∙ caudal 0.25% and 0.5% ∙ epidural test dose 0.5% with epinephrine 1:200,000 ∙ dental blocks 0.5% with epinephrine 1:200,000 (See DOSAGE AND ADMINISTRATION for additional information.) Standard textbooks should be consulted to determine the accepted procedures and techniques for the administration of MARCAINE. wEN-2916v03 Page 3 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS MARCAINE is contraindicated in obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. MARCAINE is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type or to other components of MARCAINE solutions. WARNINGS THE 0.75% CONCENTRATION OF MARCAINE IS NOT RECOMMENDED FOR OBSTETRICAL ANESTHESIA. THERE HAVE BEEN REPORTS OF CARDIAC ARREST WITH DIFFICULT RESUSCITATION OR DEATH DURING USE OF MARCAINE FOR EPIDURAL ANESTHESIA IN OBSTETRICAL PATIENTS. IN MOST CASES, THIS HAS FOLLOWED USE OF THE 0.75% CONCENTRATION. RESUSCITATION HAS BEEN DIFFICULT OR IMPOSSIBLE DESPITE APPARENTLY ADEQUATE PREPARATION AND APPROPRIATE MANAGEMENT. CARDIAC ARREST HAS OCCURRED AFTER CONVULSIONS RESULTING FROM SYSTEMIC TOXICITY, PRESUMABLY FOLLOWING UNINTENTIONAL INTRAVASCULAR INJECTION. THE 0.75% CONCENTRATION SHOULD BE RESERVED FOR SURGICAL PROCEDURES WHERE A HIGH DEGREE OF MUSCLE RELAXATION AND PROLONGED EFFECT ARE NECESSARY. LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS, PRECAUTIONS, and OVERDOSAGE.) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH. Local anesthetic solutions containing antimicrobial preservatives, i.e., those supplied in multiple-dose vials, should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentionally or unintentionally, of such preservatives. Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or wEN-2916v03 Page 4 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection. MARCAINE with epinephrine 1:200,000 or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of MARCAINE containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamineoxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. Until further experience is gained in pediatric patients younger than 12 years, administration of MARCAINE in this age group is not recommended. Mixing or the prior or intercurrent use of any other local anesthetic with MARCAINE cannot be recommended because of insufficient data on the clinical use of such mixtures. There have been reports of cardiac arrest and death during the use of MARCAINE for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of MARCAINE in this procedure is lacking. Therefore, MARCAINE is not recommended for use in this technique. MARCAINE with epinephrine 1:200,000 contains sodium metabisulfite, a sulfite that may cause allergic- type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Single-dose ampuls and single-dose vials of MARCAINE without epinephrine do not contain sodium metabisulfite. PRECAUTIONS General: The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. (See WARNINGS, ADVERSE REACTIONS, and OVERDOSAGE.) During major regional nerve blocks, the patient should have IV fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible. Epidural Anesthesia: During epidural administration of MARCAINE, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. When clinical conditions permit, the test dose should contain epinephrine (10 mcg to 15 mcg has been suggested) to serve as a warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated wEN-2916v03 Page 5 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure. The test dose should also contain 10 mg to 15 mg of MARCAINE or an equivalent amount of another local anesthetic to detect an unintended intrathecal administration. This will be evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The Test Dose formulation of MARCAINE contains 15 mg of bupivacaine and 15 mcg of epinephrine in a volume of 3 mL. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects. Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with hypotension or heartblock. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Because amide-local anesthetics such as MARCAINE are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs. Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation anesthetics. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and prompt institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene. (Consult dantrolene sodium intravenous package insert before using.) wEN-2916v03 Page 6 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use in Head and Neck Area: Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded. (See DOSAGE AND ADMINISTRATION.) Use in Ophthalmic Surgery: Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured (see also WARNINGS and Use In Head and Neck Area, above). As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses. A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local infiltration, including the conjunctiva (see INDICATIONS AND USAGE and PRECAUTIONS, General). Mixing MARCAINE with other local anesthetics is not recommended because of insufficient data on the clinical use of such mixtures. When MARCAINE 0.75% is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone should determine readiness of the patient for surgery. Use in Dentistry: Because of the long duration of anesthesia, when MARCAINE 0.5% with epinephrine is used for dental injections, patients should be cautioned about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advised not to chew solid foods or test the anesthetized area by biting or probing. Information for Patients: When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the package insert of MARCAINE. Patients receiving dental injections of MARCAINE should be cautioned not to chew solid foods or test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours). Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. wEN-2916v03 Page 7 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted. The mutagenic potential and the effect on fertility of bupivacaine hydrochloride have not been determined. Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. MARCAINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of MARCAINE at term for obstetrical anesthesia or analgesia. (See Labor and Delivery) Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are comparable to the daily maximum recommended human dose (MRHD) of 400 mg/day on a mg/m2 body surface area (BSA) basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 1/5th the MRHD on a BSA basis. In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg mg/kg/day, decreased pup survival was observed at the high dose. The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis. Labor and Delivery: SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75% MARCAINE. MARCAINE is contraindicated for obstetrical paracervical block anesthesia. Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine. It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left. Nursing Mothers: Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious wEN-2916v03 Page 8 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue nursing or not administer bupivacaine, taking into account the importance of the drug to the mother. Pediatric Use: Until further experience is gained in pediatric patients younger than 12 years, administration of MARCAINE in this age group is not recommended. Continuous infusions of bupivacaine in children have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE.) Geriatric Use: Patients over 65 years, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with MARCAINE. (See ADVERSE REACTIONS.) Elderly patients may require lower doses of MARCAINE. (See PRECAUTIONS, Epidural Anesthesia and DOSAGE AND ADMINISTRATION.) In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. (See CLINICAL PHARMACOLOGY.) This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY.) ADVERSE REACTIONS Reactions to MARCAINE are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation. The most commonly encountered acute adverse experiences which demand immediate counter-measures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Patients over 65 years, particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of MARCAINE. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. Central Nervous System Reactions: These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. wEN-2916v03 Page 9 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiovascular System Reactions: High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE.) Allergic: Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. Neurologic: The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control all of which may have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery. OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.) Management of Local Anesthetic Emergencies: The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred. If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems wEN-2916v03 Page 10 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory, and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated. Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg to 8 mg/kg and 38 mg/kg to 54 mg/kg respectively. DOSAGE AND ADMINISTRATION The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. The smallest dose and concentration required to produce the desired result should be administered. Dosages of MARCAINE should be reduced for elderly and/or debilitated patients and patients with cardiac and/or liver disease. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible. For specific techniques and procedures, refer to standard textbooks. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. MARCAINE is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION). In recommended doses, MARCAINE produces complete sensory block, but the effect on motor function differs among the three concentrations. wEN-2916v03 Page 11 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 0.25%―when used for caudal, epidural, or peripheral nerve block, produces incomplete motor block. Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently. Onset of action may be slower than with the 0.5% or 0.75% solutions. 0.5%― provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential. 0.75%―produces complete motor block. Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical anesthesia. The duration of anesthesia with MARCAINE is such that for most indications, a single dose is sufficient. Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site. Most experience to date is with single doses of MARCAINE up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization of each case. These doses may be repeated up to once every three hours. In clinical studies to date, total daily doses have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine. The dosages in Table 1 have generally proved satisfactory and are recommended as a guide for use in the average adult. These dosages should be reduced for elderly or debilitated patients. Until further experience is gained, MARCAINE is not recommended for pediatric patients younger than 12 years. MARCAINE is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (Bier Block). Use in Epidural Anesthesia: During epidural administration of MARCAINE, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated. Use only the single-dose ampuls and single-dose vials for caudal or epidural anesthesia; the multiple-dose vials contain a preservative and therefore should not be used for these procedures. Test Dose for Caudal and Lumbar Epidural Blocks: The Test Dose of MARCAINE (0.5% bupivacaine with 1:200,000 epinephrine in a 3 mL ampul) is recommended for use as a test dose when clinical conditions permit prior to caudal and lumbar epidural blocks. This may serve as a warning of unintended intravascular or subarachnoid injection. (See PRECAUTIONS.) The pulse rate and other signs should be monitored carefully immediately following each test dose administration to detect possible intravascular injection, and adequate time for onset of spinal block should be allotted to detect possible intrathecal injection. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or cardiovascular effects from the epinephrine. (See WARNINGS and OVERDOSAGE.) Use in Dentistry: The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time. (See CLINICAL PHARMACOLOGY.) The lowest effective dose should be employed and time wEN-2916v03 Page 12 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% MARCAINE with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, MARCAINE in dentistry is not recommended for pediatric patients younger than 12 years. Unused portions of solution not containing preservatives, i.e., those supplied in single-dose ampuls and single-dose vials, should be discarded following initial use. This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered. Table 1. Recommended Concentrations and Doses of MARCAINE Type of Block Local infiltration Epidural Conc. 0.25%4 0.75%2,4 0.5%4 0.25%4 (mL) up to max. 10-20 10-20 10-20 Each Dose (mg) up to max. 75-150 50-100 25-50 Motor Block1 ― complete moderate to complete partial to moderate Caudal 0.5%4 0.25%4 15-30 15-30 75-150 37.5-75 moderate to complete moderate Peripheral nerves 0.5%4 0.25%4 5 to max. 5 to max. 25 to max. 12.5 to max. moderate to complete moderate to complete Retrobulbar3 0.75%4 2-4 15-30 complete Sympathetic Dental3 0.25% 0.5% w/epi 20-50 1.8-3.6 per site 50-125 9-18 per site ― ― Epidural3 Test Dose 0.5% w/epi 2-3 10-15 (10-15 micrograms epinephrine) ― 1With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% may produce complete motor block. Intercostal nerve block with 0.25% may also produce complete motor block for intra abdominal surgery. 2For single-dose use, not for intermittent epidural technique. Not for obstetrical anesthesia. 3See PRECAUTIONS. 4Solutions with or without epinephrine. wEN-2916v03 Page 13 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED These solutions are not for spinal anesthesia. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] MARCAINE ―Solutions of MARCAINE that do not contain epinephrine may be autoclaved. Autoclave at 15-pound pressure, 121°C (250°F) for 15 minutes. NDC No. Container Fill Quantity 0.25%―Contains 2.5 mg bupivacaine hydrochloride per mL. 0409-1559-10 Single-dose vials 10 mL box of 10 0409-1559-30 Single-dose vials 30 mL box of 10 0409-1587-50 Multiple-dose vials 50 mL box of 1 0.5%―Contains 5 mg bupivacaine hydrochloride per mL. 0409-1560-10 Single-dose vials 10 mL box of 10 0409-1560-29 Single-dose vials 30 mL box of 10 0409-1610-50 Multiple-dose vials 50 mL box of 1 0.75%―Contains 7.5 mg bupivacaine hydrochloride per mL. 0409-1582-10 Single-dose vials 10 mL box of 10 0409-1582-29 Single-dose vials 30 mL box of 10 MARCAINE with epinephrine 1:200,000 (as bitartrate)―Solutions of MARCAINE that contain epinephrine should not be autoclaved and should be protected from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. NDC No. Container Fill Quantity 0.25% with epinephrine 1:200,000—Contains 2.5 mg bupivacaine hydrochloride per mL. 0409-1746-10 Single-dose vials 10 mL box of 10 0409-1746-30 Single-dose vials 30 mL box of 10 0409-1752-50 Multiple-dose vials 50 mL box of 1 0.5% with epinephrine 1:200,000—Contains 5 mg bupivacaine hydrochloride per mL. 0409-1749-03 Single-dose ampuls 3 mL box of 10 0409-1749-10 Single-dose vials 10 mL box of 10 0409-1749-29 Single-dose vials 30 mL box of 10 0409-1755-50 Multiple-dose vials 50 mL box of 1 Revised: 10/2011 Printed in USA EN-2916 Hospira, Inc., Lake Forest, IL 60045 USA Hospira wEN-2916v03 Page 14 of 14 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MarcaineTM Spinal bupivacaine hydrochloride in dextrose injection, USP STERILE HYPERBARIC SOLUTION FOR SPINAL ANESTHESIA Rx only DESCRIPTION Bupivacaine hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula: structural formula Dextrose is D-glucopyranose monohydrate and has the following structural formula: structural formula MARCAINE™ Spinal is available in sterile hyperbaric solution for subarachnoid injection (spinal block). Bupivacaine hydrochloride is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. Each mL of MARCAINE Spinal contains 7.5 mg bupivacaine hydrochloride (anhydrous) and 82.5 mg dextrose (anhydrous). The pH of this solution is adjusted to between 4.0 and 6.5 with sodium hydroxide or hydrochloric acid. The specific gravity of MARCAINE Spinal is between 1.030 and 1.035 at 25°C and 1.03 at 37°C. MARCAINE Spinal does not contain any preservatives. CLINICAL PHARMACOLOGY Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. wEN-2919v03 Page 1 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended direct intravascular injection of bupivacaine. Therefore, when epidural anesthesia with bupivacaine is considered, incremental dosing is necessary. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage. Pharmacokinetics: The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma concentration of MARCAINE, permitting the use of moderately larger total doses and sometimes prolonging the duration of action. The onset of action with MARCAINE is rapid and anesthesia is long lasting. The duration of anesthesia is significantly longer with MARCAINE than with any other commonly used local anesthetic. It has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesics is reduced. The onset of sensory blockade following spinal block with MARCAINE Spinal is very rapid (within one minute); maximum motor blockade and maximum dermatome level are achieved within 15 minutes in most cases. Duration of sensory blockade (time to return of complete sensation in the operative site or regression of two dermatomes) following a 12 mg dose averages 2 hours with or without 0.2 mg epinephrine. The time to return of complete motor ability with 12 mg MARCAINE Spinal averages 3 1/2 hours without the addition of epinephrine and 4 1/2 hours if 0.2 mg epinephrine is added. When compared to equal milligram doses of hyperbaric tetracaine, the duration of sensory blockade was the same but the time to complete motor recovery was significantly longer for tetracaine. Addition of 0.2 mg epinephrine significantly prolongs the motor blockade and time to first postoperative narcotic with MARCAINE Spinal. Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. MARCAINE with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Pharmacokinetic studies on the plasma profiles of MARCAINE after direct intravenous injection suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment wEN-2919v03 Page 2 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized. Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of MARCAINE in adults is 2.7 hours and in neonates 8.1 hours. In clinical studies, elderly patients exhibited a greater spread and higher maximal level of analgesia than younger patients. Elderly patients also reached the maximal level of analgesia more rapidly than younger patients, and exhibited a faster onset of motor blockade. The total plasma clearance was decreased and the terminal half-life was lengthened in these patients. Amide-type local anesthetics such as MARCAINE are metabolized primarily in the liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecolylxylidine is the major metabolite of MARCAINE. The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine. When administered in recommended doses and concentrations, MARCAINE does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia. INDICATIONS AND USAGE MARCAINE Spinal is indicated for the production of subarachnoid block (spinal anesthesia). Standard textbooks should be consulted to determine the accepted procedures and techniques for the administration of spinal anesthesia. CONTRAINDICATIONS MARCAINE Spinal is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type. The following conditions preclude the use of spinal anesthesia: 1. Severe hemorrhage, severe hypotension or shock and arrhythmias, such as complete heart block, which severely restrict cardiac output. 2. Local infection at the site of proposed lumbar puncture. 3. Septicemia. WARNINGS LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS and PRECAUTIONS.) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST, AND, POSSIBLY, DEATH. Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such wEN-2919v03 Page 3 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. Spinal anesthetics should not be injected during uterine contractions, because spinal fluid current may carry the drug further cephalad than desired. A free flow of cerebrospinal fluid during the performance of spinal anesthesia is indicative of entry into the subarachnoid space. However, aspiration should be performed before the anesthetic solution is injected to confirm entry into the subarachnoid space and to avoid intravascular injection. MARCAINE solutions containing epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of MARCAINE containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. Until further experience is gained in patients younger than 18 years, administration of MARCAINE in this age group is not recommended. Mixing or the prior or intercurrent use of any other local anesthetic with MARCAINE cannot be recommended because of insufficient data on the clinical use of such mixtures. PRECAUTIONS General: The safety and effectiveness of spinal anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. (See WARNINGS and ADVERSE REACTIONS.) The patient should have IV fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used. Aspiration for blood should be performed before injection and injection should be made slowly. Tolerance varies with the status of the patient. Elderly patients and acutely ill patients may require reduced doses. Reduced doses may also be indicated in patients with increased intra-abdominal pressure (including obstetrical patients), if otherwise suitable for spinal anesthesia. There should be careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness after local anesthetic injection. Restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, depression, or drowsiness may be early warning signs of central nervous system toxicity. Spinal anesthetics should be used with caution in patients with severe disturbances of cardiac rhythm, shock, or heart block. Sympathetic blockade occurring during spinal anesthesia may result in peripheral vasodilation and hypotension, the extent depending on the number of dermatomes blocked. Patients over 65 years, particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of MARCAINE Spinal. Blood pressure should, therefore, be carefully monitored especially in the early phases of anesthesia. Hypotension may be controlled by vasoconstrictors in dosages depending on the wEN-2919v03 Page 4 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda severity of hypotension and response of treatment. The level of anesthesia should be carefully monitored because it is not always controllable in spinal techniques. Because amide-type local anesthetics such as MARCAINE are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs. However, dosage recommendations for spinal anesthesia are much lower than dosage recommendations for other major blocks and most experience regarding hepatic and cardiovascular disease dose-related toxicity is derived from these other major blocks. Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation agents. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures, and dantrolene. (Consult dantrolene sodium intravenous package insert before using.) The following conditions may preclude the use of spinal anesthesia, depending upon the physician’s evaluation of the situation and ability to deal with the complications or complaints which may occur: • Pre-existing diseases of the central nervous system, such as those attributable to pernicious anemia, poliomyelitis, syphilis, or tumor. • Hematological disorders predisposing to coagulopathies or patients on anticoagulant therapy. Trauma to a blood vessel during the conduct of spinal anesthesia may, in some instances, result in uncontrollable central nervous system hemorrhage or soft tissue hemorrhage. • Chronic backache and preoperative headache. • Hypotension and hypertension. • Technical problems (persistent paresthesias, persistent bloody tap). • Arthritis or spinal deformity. • Extremes of age. • Psychosis or other causes of poor cooperation by the patient. Information for Patients: When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of spinal anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the MARCAINE Spinal package insert. Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. wEN-2919v03 Page 5 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted. The mutagenic potential and the effect on fertility of bupivacaine hydrochloride have not been determined. Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. MARCAINE Spinal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of MARCAINE Spinal at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.) Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are approximately 30-times the daily maximum recommended human dose (MRHD) of 12 mg/day on a mg dose/m2 body surface area (BSA) basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo- fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level being approximately 8-times the MRHD on a BSA basis. In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg mg/kg/day, decreased pup survival was observed at the high dose. The high dose is approximately 30-times the daily MRHD of 12 mg/day on a BSA basis. Labor and Delivery: Spinal anesthesia has a recognized use during labor and delivery. Bupivacaine hydrochloride, when administered properly, via the epidural route in doses 10 to 12 times the amount used in spinal anesthesia has been used for obstetrical analgesia and anesthesia without evidence of adverse effects on the fetus. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. It is extremely important to avoid aortocaval compression by the gravid uterus during administrations of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left. Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine. There have been reports of cardiac arrest during use of MARCAINE 0.75% solution for epidural anesthesia in obstetrical patients. The package insert for MARCAINE hydrochloride for epidural, nerve block, etc., has a more complete discussion of preparation for, and management of, this problem. These cases are compatible with systemic toxicity following unintended intravascular injection of the much larger doses recommended for epidural anesthesia and have not occurred within the dose range of wEN-2919v03 Page 6 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda bupivacaine hydrochloride 0.75% recommended for spinal anesthesia in obstetrics. The 0.75% concentration of MARCAINE is therefore not recommended for obstetrical epidural anesthesia. MARCAINE Spinal (bupivacaine hydrochloride in dextrose injection) is recommended for spinal anesthesia in obstetrics. Nursing Mothers: Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue nursing or not administer bupivacaine, taking into account the importance of the drug to the mother. Pediatric Use: Until further experience is gained in patients younger than 18 years, administration of MARCAINE Spinal in this age group is not recommended. Geriatric Use: Patients over 65 years, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing spinal anesthesia with MARCAINE Spinal. (See PRECAUTIONS, General and ADVERSE REACTIONS, Cardiovascular System.) Elderly patients may require lower doses of MARCAINE Spinal. (See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION.) In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) ADVERSE REACTIONS Reactions to bupivacaine are characteristic of those associated with other amide-type local anesthetics. The most commonly encountered acute adverse experiences which demand immediate countermeasures following the administration of spinal anesthesia are hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia. These may lead to cardiac arrest if untreated. In addition, dose-related convulsions and cardiovascular collapse may result from diminished tolerance, rapid absorption from the injection site, or from unintentional intravascular injection of a local anesthetic solution. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. Respiratory System: Respiratory paralysis or underventilation may be noted as a result of upward extension of the level of spinal anesthesia and may lead to secondary hypoxic cardiac arrest if untreated. Preanesthetic medication, intraoperative analgesics and sedatives, as well as surgical manipulation, may contribute to underventilation. This will usually be noted within minutes of the injection of spinal anesthetic solution, but because of differing maximal onset times, differing intercurrent drug usage and differing surgical manipulation, it may occur at any time during surgery or the immediate recovery period. Cardiovascular System: Hypotension due to loss of sympathetic tone is a commonly encountered extension of the clinical pharmacology of spinal anesthesia. This is more commonly observed in elderly patients, particularly those with hypertension, and patients with shrunken blood volume, shrunken interstitial fluid volume, cephalad spread of the local anesthetic, and/or mechanical obstruction of venous return. Nausea and vomiting are frequently associated with hypotensive episodes following the administration of spinal anesthesia. High doses, or inadvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, bradycardia, heart wEN-2919v03 Page 7 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda block, ventricular arrhythmias, and, possibly, cardiac arrest. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE sections.) Central Nervous System: Respiratory paralysis or underventilation secondary to cephalad spread of the level of spinal anesthesia (see Respiratory System) and hypotension for the same reason (see Cardiovascular System) are the two most commonly encountered central nervous system-related adverse observations which demand immediate countermeasures. High doses or inadvertent intravascular injection may lead to high plasma levels and related central nervous system toxicity characterized by excitement and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Neurologic: The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. Neurologic effects following spinal anesthesia may include loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness and paralysis of the lower extremities, and loss of sphincter control all of which may have slow, incomplete, or no recovery; hypotension, high or total spinal block; urinary retention; headache; backache; septic meningitis, meningismus; arachnoiditis; slowing of labor; increased incidence of forceps delivery; shivering; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid; and fecal and urinary incontinence. Allergic: Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and, possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. Other: Nausea and vomiting may occur during spinal anesthesia. OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use or to underventilation (and perhaps apnea) secondary to upward extension of spinal anesthesia. Hypotension is commonly encountered during the conduct of spinal anesthesia due to relaxation of sympathetic tone, and sometimes, contributory mechanical obstruction of venous return. Management of Local Anesthetic Emergencies: The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to a high or total spinal, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred. If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems wEN-2919v03 Page 8 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). Hypotension due to sympathetic relaxation may be managed by giving intravenous fluids (such as isotonic saline or lactated Ringer’s solution), in an attempt to relieve mechanical obstruction of venous return, or by using vasopressors (such as ephedrine which increases the force of myocardial contractions) and, if indicated, by giving plasma expanders or whole blood. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated. Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to a high or total spinal may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary. Recovery has been reported after prolonged resuscitative efforts. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg to 8 mg/kg and 38 mg/kg to 54 mg/kg respectively. DOSAGE AND ADMINISTRATION The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. The smallest dose and concentration required to produce the desired result should be administered. Dosages of MARCAINE Spinal should be reduced for elderly and debilitated patients and patients with cardiac and/or liver disease. For specific techniques and procedures, refer to standard textbooks. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. MARCAINE Spinal is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION). wEN-2919v03 Page 9 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The extent and degree of spinal anesthesia depend upon several factors including dosage, specific gravity of the anesthetic solution, volume of solution used, force of injection, level of puncture, and position of the patient during and immediately after injection. Seven and one-half mg (7.5 mg or 1 mL) MARCAINE Spinal has generally proven satisfactory for spinal anesthesia for lower extremity and perineal procedures including TURP and vaginal hysterectomy. Twelve mg (12 mg or 1.6 mL) has been used for lower abdominal procedures such as abdominal hysterectomy, tubal ligation, and appendectomy. These doses are recommended as a guide for use in the average adult and may be reduced for the elderly or debilitated patients. Because experience with MARCAINE Spinal is limited in patients below the age of 18 years, dosage recommendations in this age group cannot be made. Obstetrical Use: Doses as low as 6 mg bupivacaine hydrochloride have been used for vaginal delivery under spinal anesthesia. The dose range of 7.5 mg to 10.5 mg (1 mL to 1.4 mL) bupivacaine hydrochloride has been used for Cesarean section under spinal anesthesia. In recommended doses, MARCAINE Spinal produces complete motor and sensory block. Unused portions of solutions should be discarded following initial use. MARCAINE Spinal should be inspected visually for discoloration and particulate matter prior to administration; solutions which are discolored or which contain particulate matter should not be administered. HOW SUPPLIED Single-dose ampuls of 2 mL (15 mg bupivacaine hydrochloride with 165 mg dextrose), is supplied as follows: NDC No. Container Fill Quantity 0409-1761-02 0409-1761-62 Uni-Amp™ Uni-Amp™ 2 mL 2 mL package of 10 bulk package of 800 Store at 20 to 25ºC (68 to 77ºF). [See USP Controlled Room Temperature.] MARCAINE Spinal solution may be autoclaved once at 15 pound pressure, 121°C (250°F) for 15 minutes. Do not administer any solution which is discolored or contains particulate matter. Revised: 10/2011 EN-2919 Hospira, Inc., Lake Forest, IL 60045 USA Hospira wEN-2919v03 Page 10 of 10 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bupivacaine HCl 0.5% with epinephrine 1:200,000 (as bitartrate) (bupivacaine hydrochloride and epinephrine injection, USP) THIS SOLUTION IS INTENDED FOR DENTAL USE. Rx only DESCRIPTION Bupivacaine hydrochloride is (±) -1-Butyl-2´,6´-pipecoloxylidide monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula: structural formula Epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol. It has the following structural formula: structural formula BUPIVACAINE HCl is available in a sterile isotonic solution with epinephrine (as bitartrate) 1:200,000. Solutions of BUPIVACAINE HCl containing epinephrine may not be autoclaved. BUPIVACAINE HCl is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. CLINICAL PHARMACOLOGY BUPIVACAINE HCl stabilizes the neuronal membrane and prevents the initiation and transmission of nerve impulses, thereby effecting local anesthesia. The onset of action following dental injections is usually 2 to 10 minutes and anesthesia may last two or three times longer than lidocaine and mepivacaine for dental use, in many patients up to 7 hours. The duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000. It has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesic is reduced. After injection of BUPIVACAINE HCl for caudal, epidural or peripheral nerve block in man, peak levels of BUPIVACAINE HCl in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours. Because of its amide structure, BUPIVACAINE HCl is not detoxified by plasma esterases but is detoxified, via conjugation with glucuronic acid, in the wEN-2920v01 Page 1 of 6 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda liver. When administered in recommended doses and concentrations, BUPIVACAINE HCl does not ordinarily produce irritation or tissue damage, and does not cause methemoglobinemia. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine. Therefore, incremental dosing is necessary. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state. INDICATIONS AND USAGE BUPIVACAINE HCl is indicated for the production of local anesthesia for dental procedures by infiltration injection or nerve block in adults. BUPIVACAINE HCl is not recommended for children. CONTRAINDICATIONS BUPIVACAINE HCl is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type or to other components of BUPIVACAINE HCl solutions. WARNINGS LOCAL ANESTHETICS SHOULD BE EMPLOYED ONLY BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS and PRECAUTIONS.) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH. Small doses of local anesthetics injected into the head and neck area, as small as nine to eighteen milligrams, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression, and/or respiratory arrest, cardiovascular stimulation or depression and cardiac arrest have been reported. Reactions resulting in fatalities have occurred on rare occasions. In a few cases, resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. wEN-2920v01 Page 2 of 6 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded (see DOSAGE AND ADMINISTRATION). It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular injection. However, a negative aspiration does not ensure against an intravascular injection. Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in the absence of a history of hypersensitivity. This solution, which contains a vasoconstrictor, should be used with extreme caution for patients whose medical history and physical evaluation suggest the existence of hypertension, arteriosclerotic heart disease, cerebral vascular insufficiency, heart block, thyrotoxicosis and diabetes, etc., as well as patients receiving drugs likely to produce alterations in blood pressure. BUPIVACAINE HCl with epinephrine 1:200,000 or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of BUPIVACAINE HCl containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. Until further experience is gained in children younger than 12 years, administration of BUPIVACAINE HCl in this age group is not recommended. Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. PRECAUTIONS The safety and effectiveness of local anesthetics depend upon proper dosage, correct technique, adequate precautions, and readiness for emergencies. The lowest dosage that gives effective anesthesia should be used in order to avoid high plasma levels and serious systemic side effects. Injection of repeated doses of BUPIVACAINE HCl may cause significant increase in blood levels with each additional dose, due to accumulation of the drug or its metabolites or due to slow metabolic degradation. Tolerance varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with age and physical condition. Because of the long duration of anesthesia, when BUPIVACAINE HCl 0.5% with epinephrine is used for dental injections, patients should be cautioned about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advised not to chew solid foods or test the anesthetized area by biting or probing. Changes in sensorium, such as excitation, disorientation, drowsiness, may be early indications of a high blood level of the drug and may occur following inadvertent intravascular administration or rapid absorption of BUPIVACAINE HCl. Solutions containing a vasoconstrictor should be used cautiously in areas with limited blood supply, in the presence of diseases that may adversely affect the patient's cardiovascular system, or in patients with peripheral vascular disease. Caution is advised in administration of repeat doses of BUPIVACAINE HCl to patients with severe liver disease. wEN-2920v01 Page 3 of 6 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. Drug Interactions: See WARNINGS concerning solutions containing a vasoconstrictor. If sedatives are employed to reduce patient apprehension, use reduced doses, since local anesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect. BUPIVACAINE HCl should be used cautiously in persons with known drug allergies or sensitivities, particularly to the amide-type local anesthetics. Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of chloroform, halothane, cyclopropane, trichloroethylene, or other related agents. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. Information for Patients: When appropriate, the dentist should discuss information including adverse reactions in the package insert for BUPIVACAINE HCl. Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted. The mutagenic potential and the effect on fertility of bupivacaine hydrochloride have not been determined. Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. BUPIVACAINE HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of BUPIVACAINE HCl at term for obstetrical anesthesia or analgesia. Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are approximately 4-times the daily maximum recommended human dose (MRHD) of 90 mg/day on a mg dose/m2 body surface area (BSA) basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo- fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level being a comparable dose to the MRHD on a BSA basis. In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg mg/kg/day, decreased pup survival was observed at the high dose. The high dose is approximately 4-times the daily MRHD of 90 mg/day on a BSA basis. wEN-2920v01 Page 4 of 6 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers: It is not known whether local anesthetic drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when local anesthetics are administered to a nursing woman. Pediatric Use: Until further experience is gained in children younger than 12 years, administration of BUPIVACAINE HCl in this age group is not recommended. ADVERSE REACTIONS Reactions to BUPIVACAINE HCl are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, inadvertent intravascular injection, or slow metabolic degradation. Excessive plasma levels of the amide-type local anesthetics cause systemic reactions involving the central nervous system and the cardiovascular system. The central nervous system effects are characterized by excitation or depression. The first manifestation may be nervousness, dizziness, blurred vision, or tremors, followed by drowsiness, convulsions, unconsciousness, and possibly respiratory arrest. Since excitement may be transient or absent, the first manifestation may be drowsiness, sometimes merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, constriction of the pupils, or tinnitus. The cardiovascular manifestations of excessive plasma levels may include depression of the myocardium, blood pressure changes (usually hypotension), and cardiac arrest. Allergic reactions, which may be due to hypersensitivity, idiosyncrasy, or diminished tolerance, are characterized by cutaneous lesions (e.g., urticaria), edema, and other manifestations of allergy. Detection of sensitivity by skin testing is of doubtful value. Transient facial swelling and puffiness may occur near the injection site. Treatment of Reactions: Toxic effects of local anesthetics require symptomatic treatment; there is no specific cure. The dentist should be prepared to maintain an airway and to support ventilation with oxygen and assisted or controlled respiration as required. Supportive treatment of the cardiovascular system includes intravenous fluids and, when appropriate, vasopressors (preferably those that stimulate the myocardium). Convulsions may be controlled with oxygen and intravenous administration, in small increments, of a barbiturate, as follows: preferably, an ultra-short-acting barbiturate such as thiopental or thiamylal; if this is not available, a short-acting barbiturate (e.g., secobarbital or pentobarbital) or diazepam. Intravenous barbiturates or anticonvulsant agents should only be administered by those familiar with their use. DOSAGE AND ADMINISTRATION As with all local anesthetics, the dosage varies and depends upon the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, individual tolerance, and the technique of anesthesia. The lowest dosage needed to provide effective anesthesia should be administered. For specific techniques and procedures, refer to standard textbooks. The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time (see CLINICAL PHARMACOLOGY). The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL wEN-2920v01 Page 5 of 6 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda injections of 0.5% BUPIVACAINE HCl with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, BUPIVACAINE HCl in dentistry is not recommended for children younger than 12 years. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HOW SUPPLIED Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from light. 0.5% Bupivacaine hydrochloride with epinephrine 1:200,000 (as bitartrate) – Sterile isotonic solutions containing sodium chloride. Each 1 mL contains 5 mg bupivacaine hydrochloride and 0.0091 mg epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, and 0.1 mg edetate calcium disodium as stabilizer. The pH of these solutions is adjusted with sodium hydroxide or hydrochloric acid. Solutions of BUPIVACAINE HCl that contain epinephrine should not be autoclaved and should be protected from light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. This product is latex-free. NDC 0409-7600-01 1.8 mL cartridges, containers of 50, to fit the CarpuleTM aspirator. Revised: 10/2011 EN-2920 Hospira, Inc., Lake Forest, IL 60045 USA Hospira wEN-2920v01 Page 6 of 6 Reference ID: 3079122 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:06.209804	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016964s070lbl.pdf', 'application_number': 16964, 'submission_type': 'SUPPL ', 'submission_number': 70}
10,945	NDA 16968/S-029 Page 4 MIOSTAT† (CARBACHOL INTRAOCULAR SOLUTION, USP) 0.01% DESCRIPTION: MIOSTAT† (carbachol intraocular solution, USP) is a sterile balanced salt solution of carbachol for intraocular injection. The active ingredient is represented by the chemical structure: structural formula Established name: Carbachol Chemical name: Ethanaminium, 2-[(aminocarbonyl)oxy]-N,N,Ntrimethyl-, chloride. Molecular Formula: C6H15CIN2O2 Molecular Weight: 182.65 Each mL contains: Active: carbachol 0.01%. Inactives: sodium chloride 0.64%, potassium chloride 0.075%, calcium chloride dehydrate 0.048%, magnesium chloride hexahydrate 0.03%, sodium acetate trihydrate 0.39%, sodium citrate dihydrate 0.17%, sodium hydroxide and/or hydrochloric acid (to adjust pH) and Water for Injection. pH range is 6.5-7.5. CLINICAL PHARMACOLOGY: Carbachol is a potent cholinergic (parasympathomimetic) agent which produces constriction of the iris and ciliary body resulting in reduction in intraocular pressure. The exact mechanism by which carbachol lowers intraocular pressure is not precisely known. INDICATIONS AND USAGE: Intraocular use for obtaining miosis during surgery. In addition, MIOSTAT (carbachol intraocular solution, USP) reduces the intensity of intraocular pressure elevation in the first 24 hours after cataract surgery. CONTRAINDICATIONS: Should not be used in those persons showing hypersensitivity to any of the components of this preparation. WARNINGS For single-dose intraocular use only. Discard unused portion. Intraocular carbachol 0.01% should be used with caution in patients with acute cardiac failure, bronchial asthma, peptic ulcer, hyperthyroidism, G.I. spasm, urinary tract obstruction and Parkinson's disease. The vial stopper contains natural rubber (latex) which may cause severe allergic reactions. Reference ID: 3875885 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16968/S-029 Page 5 PRECAUTIONS: Use only if the container is undamaged. Carcinogenesis: Studies in animals to evaluate the carcinogenic potential have not been conducted. Pregnancy: Category C. There are no adequate and well-controlled studies in pregnant women. MIOSTAT (carbachol intraocular solution, USP) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known if this medication is excreted in breast milk. Exercise caution when administering to a nursing woman. Pediatric Use: Safety and efficacy in pediatric patients have not been established. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients. ADVERSE REACTIONS Ocular: Corneal clouding, persistent bullous keratopathy, retinal detachment and postoperative iritis following cataract extraction have been reported. Systemic: Side effects such as flushing, sweating, epigastric distress, abdominal cramps, tightness in urinary bladder, and headache have been reported with topical or systemic application of carbachol. The following additional reactions have been identified during post-approval use of MIOSTAT (carbachol intraocular solution, USP) in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to MIOSTAT, or a combination of these factors, include: corneal edema, drug effect prolonged (miosis), eye inflammation, eye pain, intraocular pressure increased, ocular hyperemia, vision blurred, visual impairment, and vomiting. DOSAGE AND ADMINISTRATION: Aseptically remove the sterile vial from the blister package by peeling the backing paper and dropping the vial onto a sterile tray. Withdraw the contents into a dry sterile syringe, and replace the needle with an atraumatic cannula prior to intraocular instillation. No more than one-half milliliter should be gently instilled into the anterior chamber for the production of satisfactory miosis. It may be instilled before or after securing sutures. Miosis is usually maximal within two to five minutes after application. HOW SUPPLIED: In a 2.0 mL glass vial with a 1.5 mL fill, grey butyl stopper and aluminum seal packaged twelve to a carton. NDC 0065-0023-15 STORAGE: Store at 15° - 30°C (59° - 86°F). Distributed by: Alcon Laboratories, Inc. Reference ID: 3875885 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16968/S-029 Page 6 Fort Worth, Texas 76134 USA © 2002, 2003, 2015 Novartis Revised: -July 2015 † Trademark of Novartis Reference ID: 3875885 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:06.213697	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016968s029lbl.pdf', 'application_number': 16968, 'submission_type': 'SUPPL ', 'submission_number': 29}
10,944	NDA 16-968/S-020 Page 3 M IOSTAT® (CARBACHOLINTRAOCULAR SOLUTION, USP) 0.01% DESCRIPTION: MIOSTAT® (carbachol intraocular solution, USP) is a sterile balanced salt solution of carbachol for intraocular injection. The active ingredient is represented by the chemical structure: Established name: Carbachol Chemical name: Ethanaminium, 2-[(aminocarbonyl)oxy]-N,N,N trimethyl-, chloride. Molecular Formula: C6H15ClN2O2 Molecular Weight: 182.65 Each mL contains: Active: carbachol 0.01 %. Inactives: sodium chloride 0.64%, potassium chloride 0.075%, calcium chloride dihydrate 0.048%, magnesium chloride hexahydrate 0.03%, sodium acetate trihydrate 0.39%, sodium citrate dihydrate 0.17%, sodium hydroxide and/or hydrochloric acid (to adjust pH) and Water for Injection. CLINICAL PHARMACOLOGY: Carbachol is a potent cholinergic (parasympathomimetic) agent which produces constriction of the iris and ciliary body resulting in reduction in intraocular pressure. The exact mechanism by which carbachol lowers intraocular pressure is not precisely known. INDICATIONS AND USAGE: Itraocular use for obtaining miosis during surgery. In addition, MIOSTAT (carbachol intraocular solution, USP) reduces the intensity of intraocular pressure elevation in the first 24 hours after cataract surgery. CONTRAINDICATIONS: Should not be used in those persons showing hypersensitivity to any of the components of this preparation. WARNINGS: For single-dose intraocular use only. Discard unused portion. Intraocular carbachol 0.01 % should be used with caution in patients with acute cardiac failure, bronchial asthma, peptic ulcer, hyperthyroidism, G.I. spasm, urinary tract obstruction and Parkinson’s disease. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-968/S-020 Page 4 PRECAUTIONS: Carcinogenesis: Studies in animals to evaluate the carcinogenic potential have not been conducted. Pregnancy: Category C. There are no adequate and well-controlled studies in pregnant women. MIOSTAT®(carbachol intraocular solution, USP) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known if this medication is excreted in breast milk. Exercise caution when administering to a nursing woman. Pediatric Use: Safety and efficacy in pediatric patients have not been established. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients. ADVERSE REACTIONS: Ocular: Corneal clouding, persistent bullous keratopathy, retinal detachment and postoperative iritis following cataract extraction have been reported. Systemic: Side effects such as flushing, sweating, epigastric distress, abdominal cramps, tightness in urinary bladder, and headache have been reported with topical or systemic application of carbachol. DOSAGE AND ADMINISTRATION: Aseptically remove the sterile vial from the blister package by peeling the backing paper and dropping the vial onto a sterile tray. Withdraw the contents into a dry sterile syringe, and replace the needle with an atraumatic cannula prior to intraocular instillation. No more than one-half milliliter should be gently instilled into the anterior chamber for the production of satisfactory miosis. It may be instilled before or after securing sutures. Miosis is usually maximal within two to five minutes after application. HOW SUPPLIED: In 1.5 mL sterile glass vials packaged twelve to a carton. NDC 0065-0023-15 STORAGE: Store at controlled room temperature 15° - 30°C (59° - 86°F). Rx Only Alcon Alcon Laboratories, Inc. Fort Worth, Texas 76134 USA Printed in USA © 2002 Alcon Laboratories, Inc Revised: April 2002 340029-0402 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:06.360809	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16968slr020_Miostat_lbl.pdf', 'application_number': 16968, 'submission_type': 'SUPPL ', 'submission_number': 20}
10,947	ANCOBON® (flucytosine) CAPSULES DESCRIPTION Ancobon (flucytosine), an antifungal agent, is available as 250mg and 500mg capsules for oral administration. Each capsule also contains corn starch, lactose and talc. Gelatin capsule shells contain parabens (butyl, methyl, propyl) and sodium propionate, with the following dye systems: 250-mg capsules — black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 and titanium dioxide; 500mg capsules — black iron oxide and titanium dioxide. Chemically, flucytosine is 5-fluorocytosine, a fluorinated pyrimidine which is related to fluorouracil and floxuridine. It is a white to off-white crystalline powder with a molecular weight of 129.09 and the following structural formula: CLINICAL PHARMACOLOGY Flucytosine is rapidly and virtually completely absorbed following oral administration. Ancobon is not metabolized significantly when given orally to man. Bioavailability estimated by comparing the area under the curve of serum concentrations after oral and intravenous administration showed 78% to 89% absorption of the oral dose. Peak serum concentrations of 30 to 40 µg/mL were reached within 2 hours of administration of a 2g oral dose to normal subjects. Other studies revealed mean serum concentrations of approximately 70 to 80 µg/mL 1 to 2 hours after a dose in patients with normal renal function receiving a 6-week regimen of flucytosine (150 mg/kg/day given in divided doses every 6 hours) in combination with amphotericin B. The half-life in the majority of healthy subjects ranged between 2.4 and 4.8 hours. Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. More than 90% of the total radioactivity after oral administration was recovered in the urine as intact drug. Flucytosine is deaminated (probably by gut bacteria) to 5-fluorouracil. The area under the curve (AUC) ratio of 5-fluorouracil to flucytosine is 4%. Approximately 1% of the dose is present in the urine as the α-fluoro-ß-ureido-propionic acid metabolite. A small portion of the dose is excreted in the feces. WARNING Use with extreme caution in patients with impaired renal function. Close monitoring of hematologic, renal and hepatic status of all patients is essential. These instructions should be thoroughly reviewed before administration of Ancobon. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The half-life of flucytosine is prolonged in patients with renal insufficiency; the average half-life in nephrectomized or anuric patients was 85 hours (range: 29.9 to 250 hours). A linear correlation was found between the elimination rate constant of flucytosine and creatinine clearance. In vitro studies have shown that 2.9% to 4% of flucytosine is protein-bound over the range of therapeutic concentrations found in the blood. Flucytosine readily penetrates the blood-brain barrier, achieving clinically significant concentrations in cerebrospinal fluid. Pharmacokinetics in Pediatric Patients Limited data are available regarding the pharmacokinetics of Ancobon administered to neonatal patients being treated for systemic candidiasis. After five days of continuous therapy, median peak levels in infants were 19.6 µg/mL, 27.7 µg/mL, and 83.9 µg/mL at doses of 25 mg/kg (N=3), 50 mg/kg (N=4), and 100 mg/kg (N=3), respectively. Mean time to peak serum levels was of 2.5 ± 1.3 hours, similar to that observed in adult patients. A good deal of interindividual variability was noted, which did not correlate with gestational age. Some patients had serum levels > 100 µg/mL, suggesting a need for drug level monitoring during therapy. In another study, serum concentrations were determined during flucytosine therapy in two patients (total assays performed =10). Median serum flucytosine concentrations at steady state were calculated to be 57 ± 10 µg/mL (doses of 50 to 125 mg/kg/day, normalized to 25 mg/kg per dose for comparison). In three infants receiving flucytosine 25 mg/kg/day (four divided doses), a median flucytosine half-life of 7.4 hours was observed, approximately double that seen in adult patients. The concentration of flucytosine in the cerebrospinal fluid of one infant was 43 µg/mL 3 hours after a 25 mg oral dose, and ranged from 20 to 67 mg/L in another neonate receiving oral doses of 120 to 150 mg/kg/day. MICROBIOLOGY Mechanism of Action Flucytosine is taken up by fungal organisms via the enzyme cytosine permease. Inside the fungal cell, flucytosine is rapidly converted to fluorouracil by the enzyme cytosine deaminase. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis by being falsely incorporated into fungal RNA or interfere with the biosynthesis of fungal DNA through the inhibition of the enzyme thymidylate synthetase. Activity In Vitro Flucytosine exhibited activity against Candida species and Cryptococcus neoformans. In vitro activity of flucytosine is affected by the test conditions. It is essential to follow the approved standard method guidelines.1 Susceptibility Tests Cryptococcus neoformans: No interpretive criteria have been established for Cryptococcus neoformans1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Candida: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of yeasts to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 with standardized inoculum concentrations and standardized concentrations of flucytosine powder. The MIC values should be interpreted according to the following criteria: MIC (µg/mL) Interpretation ≤4 Susceptible (S) 8-16 Intermediate (I) ≥32 Resistant (R) A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected. Because of other significant host factors, in vitro susceptibility may not correlate with clinical outcomes. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard flucytosine powder should provide the following MIC values: Acceptable ranges of MICs (µg/mL) for control strains for 48-hour reference broth macrodilution testing: Microorganism MIC (µg/mL) [% of data included] Candida parapsilosis ATCC 22019 0.12-0.5 [98.6%] Candida krusei ATCC 6258 4.0-16 [96.8%] Acceptable ranges of MICs (µg/mL) for control strains for 24-hour and 48-hour reference broth microdilution testing: MIC (µg/mL) ranges for microdilution testing 24-hour 48-hour Microorganism Range Mode % of data Included Range Mode % of data included This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Candida parapsilosis ATCC 22019 0.06-0.25 0.12 99% 0.12-0.5 0.25 98% Candida krusei ATCC 6258 4.0-16 8.0 98% 8.0-32 16 99% Drug Resistance Flucytosine resistance may arise from a mutation of an enzyme necessary for the cellular uptake or metabolism of flucytosine or from an increased synthesis of pyrimidines, which compete with the active metabolites of flucytosine (fluorinated antimetabolites). Resistance to flucytosine has been shown to develop during monotherapy after prolonged exposure to the drug. Drug Combination Antifungal synergism between flucytosine and polyene antibiotics, particularly amphotericin B has been reported in vitro. Ancobon is usually administered in combination with amphotericin B due to lack of cross-resistance and reported synergistic activity of both drugs. INDICATIONS AND USAGE Ancobon is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine. Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported. Ancobon should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Ancobon (See MICROBIOLOGY). CONTRAINDICATIONS Ancobon should not be used in patients with a known hypersensitivity to the drug. WARNINGS Ancobon must be given with extreme caution to patients with impaired renal function. Since Ancobon is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Ancobon serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drug. Ancobon must be given with extreme caution to patients with bone marrow depression. Patients may be more prone to depression of bone marrow function if they: 1) have a hematologic disease, 2) are being treated with radiation or drugs which depress bone marrow, or 3) have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during therapy. PRECAUTIONS General Before therapy with Ancobon is instituted, electrolytes (because of hypokalemia) and the hematologic and renal status of the patient should be determined (see WARNINGS). Close monitoring of the patient during therapy is essential. Laboratory Tests Since renal impairment can cause progressive accumulation of the drug, blood concentrations and kidney function should be monitored during therapy. Hematologic status (leucocyte and thrombocyte count) and liver function (alkaline phosphatase, SGOT and SGPT) should be determined at frequent intervals during treatment as indicated. Drug Interactions Cytosine arabinoside, a cytostatic agent, has been reported to inactivate the antifungal activity of Ancobon by competitive inhibition. Drugs which impair glomerular filtration may prolong the biological half-life of flucytosine. Drug/Laboratory Test Interactions Measurement of serum creatinine levels should be determined by the Jaffé reaction, since Ancobon does not interfere with the determination of creatinine values by this method. Most automated equipment for measurement of creatinine makes use of the Jaffé reaction. Carcinogenesis, Mutagenesis, Impairment of Fertility Flucytosine has not undergone adequate animal testing to evaluate carcinogenic potential. The mutagenic potential of flucytosine was evaluated in Ames-type studies with five different mutants of S. typhimurium and no mutagenicity was detected in the presence or absence of activating enzymes. Flucytosine was nonmutagenic in three different repair assay systems (i.e., rec, uvr and pol). There have been no adequate trials in animals on the effects of flucytosine on fertility or reproductive performance. The fertility and reproductive performance of the offspring (F1 generation) of mice treated with 100 mg/kg/day (345 mg/M2/day or 0.059 times the human dose), 200 mg/kg/day (690 mg/M2/day or 0.118 times the human dose) or 400 mg/kg/day (1380 mg/M2/day or 0.236 times the human dose) of flucytosine on days 7 to 13 of gestation was studied; the in utero treatment had no adverse effect on the fertility or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reproductive performance of the offspring. Pregnancy: Teratogenic Effects. Pregnancy Category C Flucytosine was shown to be teratogenic (vertebral fusions) in the rat at doses of 40 mg/kg/day (298 mg/M2/day or 0.051 times the human dose) administered on days 7 to 13 of gestation. At higher doses (700 mg/kg/day; 5208 mg/M2/day or 0.89 times the human dose administered on days 9 to 12 of gestation), cleft lip and palate and micrognathia were reported. Flucytosine was not teratogenic in rabbits up to a dose of 100 mg/kg/day (1423 mg/M2/day or 0.243 times the human dose) administered on days 6 to 18 of gestation. In mice, 400 mg/kg/day of flucytosine (1380 mg/M2/day or 0.236 times the human dose) administered on days 7 to 13 of gestation was associated with a low incidence of cleft palate that was not statistically significant. There are no adequate and well-controlled studies in pregnant women. Ancobon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Ancobon, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The efficacy and safety of Ancobon have not been systematically studied in pediatric patients. A small number of neonates have been treated with 25 to 200 mg/kg/day of flucytosine, with and without the addition of amphotericin B, for systemic candidiasis. No unexpected adverse reactions were reported in these patients. It should be noted, however, that hypokalemia and acidemia were reported in one patient who received flucytosine in combination with amphotericin B, and anemia was observed in a second patient who received flucytosine alone. Transient thrombocytopenia was noted in two additional patients, one of whom also received amphotericin B. ADVERSE REACTIONS The adverse reactions which have occurred during treatment with Ancobon are grouped according to organ system affected. Cardiovascular: Cardiac arrest, myocardial toxicity, ventricular dysfunction. Respiratory: Respiratory arrest, chest pain, dyspnea. Dermatologic: Rash, pruritus, urticaria, photosensitivity. Gastrointestinal: Nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal hemorrhage, acute hepatic injury with possible fatal outcome in debilitated patients, hepatic dysfunction, jaundice, ulcerative colitis, bilirubin elevation, increased hepatic enzymes. Genitourinary: Azotemia, creatinine and BUN elevation, crystalluria, renal failure. Hematologic: Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia Neurologic: Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda neuropathy, pyrexia, vertigo, sedation, convulsions. Psychiatric: Confusion, hallucinations, psychosis. Miscellaneous: Fatigue, hypoglycemia, hypokalemia, weakness, allergic reactions, Lyell’s syndrome. OVERDOSAGE There is no experience with intentional overdosage. It is reasonable to expect that overdosage may produce pronounced manifestations of the known clinical adverse reactions. Prolonged serum concentrations in excess of 100 µg/mL may be associated with an increased incidence of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis). In the management of overdosage, prompt gastric lavage or the use of an emetic is recommended. Adequate fluid intake should be maintained, by the intravenous route if necessary, since Ancobon is excreted unchanged via the renal tract. The hematologic parameters should be monitored frequently; liver and kidney function should be carefully monitored. Should any abnormalities appear in any of these parameters, appropriate therapeutic measures should be instituted. Since hemodialysis has been shown to rapidly reduce serum concentrations in anuric patients, this method may be considered in the management of overdosage. DOSAGE AND ADMINISTRATION The usual dosage of Ancobon is 50 to 150 mg/kg/day administered in divided doses at 6- hour intervals. Nausea or vomiting may be reduced or avoided if the capsules are given a few at a time over a 15-minute period. If the BUN or the serum creatinine is elevated, or if there are other signs of renal impairment, the initial dose should be at the lower level (see WARNINGS). Ancobon should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Ancobon (See MICROBIOLOGY). HOW SUPPLIED Capsules, 250 mg (gray and green), imprinted ANCOBON® 250 ICN, bottles of 100 (NDC 0187-3554-10). Capsules, 500 mg (gray and white), imprinted ANCOBON® 500 ICN, bottles of 100 (NDC 0187-3555-10). Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). REFERENCES 1: Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Second Edition. NCCLS Document M27-A2, 2002 Volume 22, No 15, NCCLS, Wayne, PA, August 2002. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Valeant Pharmaceuticals International 3300 Hyland Avenue Costa Mesa, California 92626 714-545-0100 3355497EX05 Rev. May 2006 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:06.478962	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf', 'application_number': 17001, 'submission_type': 'SUPPL ', 'submission_number': 27}
10,948	PAVULON® (pancuronium bromide) injection NOT FOR USE IN NEONATES CONTAINS BENZYL ALCOHOL THIS DRUG SHOULD BE ADMINISTERED BY ADEQUATELY TRAINED INDIVIDUALS FAMILIAR WITH ITS ACTIONS, CHARACTERISTICS, AND HAZARDS. DESCRIPTION: PAVULON® (pancuronium bromide) injection is a nondepolarizing neuromuscular structural formula blocking agent chemically designated as the aminosteroid 2 ß, 16 ß - dipiperidino-5α-androstane 3α, 17-ß diol diacetate dimethobromide. The structural formula is: PAVULON® is supplied as a sterile, isotonic, nonpyrogenic solution for injection. Each mL contains 1 mg or 2 mg pancuronium bromide, 2 mg sodium acetate and 1% benzyl alcohol as preservative. The solution is adjusted to isotonicity with sodium chloride and to a pH of 4 with acetic acid and/or sodium hydroxide; water is used as the solvent. CLINICAL PHARMACOLOGY: PAVULON® is a nondepolarizing neuromuscular blocking agent possessing all of the characteristic pharmacological actions of this class of drugs (curariform). It acts by competing for cholinergic receptors at the motor end-plate. The antagonism to acetylcholine is inhibited and neuromuscular block is reversed by anticholinesterase agents such as pyridostigmine, neostigmine, and edrophonium. PAVULON® is approximately 1/3 less potent than vecuronium and approximately 5 times as potent as d-tubocurarine; the duration of neuromuscular blockade produced by PAVULON® is longer than that of vecuronium at initially equipotent doses. The ED95 (dose required to produce 95% suppression of muscle twitch response) is approximately Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 0.05 mg/kg under balanced anesthesia and 0.03 mg/kg under halothane anesthesia. These doses produce effective skeletal muscle relaxation (as judged by time from maximum effect to 25% recovery of control twitch height) for approximately 22 minutes; the duration from injection to 90% recovery of control twitch height is approximately 65 minutes. The intubating dose of 0.1 mg/kg (balanced anesthesia) will effectively abolish twitch response within approximately 4 minutes; time from injection to 25% recovery from this dose is approximately 100 minutes. Supplemental doses to maintain muscle relaxation slightly increase the magnitude of block and significantly increase the duration of block. The use of a peripheral nerve stimulator is of benefit in assessing the degree of neuromuscular blockade. The most characteristic circulatory effects of pancuronium, studied under halothane anesthesia, are a moderate rise in heart rate, mean arterial pressure and cardiac output; systemic vascular resistance is not changed significantly and central venous pressure may fall slightly. The heart rate rise is inversely related to the rate immediately before administration of pancuronium, is blocked by prior administration of atropine, and appears unrelated to the concentration of halothane or dose of pancuronium. Data on histamine assays and available clinical experience indicate that hypersensitivity reactions such as bronchospasm, flushing, redness, hypotension, tachycardia, and other reactions commonly associated with histamine release are rare. (see ADVERSE REACTIONS). Pharmacokinetics: The elimination half-life of pancuronium has been reported to range between 89–161 minutes. The volume of distribution ranges from 241–280 mL/kg and plasma clearance is approximately 1.1–1.9 mL/minute/kg. Approximately 40% of the total dose of pancuronium has been recovered in urine as unchanged pancuronium and its metabolites while approximately 11% has been recovered in bile. As much as 25% of an injected dose may be recovered as 3-hydroxy metabolite, which is half as potent a blocking agent as pancuronium. Less than 5% of the injected dose is recovered as 17-hydroxy metabolite and 3.17-dihydroxy metabolite, which have been judged to be approximately 50 times less potent than pancuronium. Pancuronium exhibits strong Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda binding to gamma globulin and moderate binding to albumin. Approximately 13% is unbound to plasma protein. In patients with cirrhosis the volume of distribution is increased by approximately 50%, the plasma clearance is decreased by approximately 22% and the elimination half-life is doubled. Similar results were noted in patients with biliary obstruction, except that plasma clearance was less than half the normal rate. The initial total dose to achieve adequate relaxation may thus be high in patients with hepatic and/or biliary tract dysfunction, while the duration of action is greater than usual. The elimination half-life is doubled and the plasma clearance is reduced by approximately 60% in patients with renal failure. The volume of distribution is variable, and in some cases elevated. The rate of recovery of neuromuscular blockade, as determined by peripheral nerve stimulation is variable and sometimes very much slower than normal. INDICATIONS AND USAGE: PAVULON® (pancuronium bromide) injection is indicated as an adjunct to general anesthesia, to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. CONTRAINDICATIONS: PAVULON® is contraindicated in patients known to be hypersensitive to the drug. PAVULON® is contraindicated for use in neonates, including premature infants, because the formulation contains benzyl alcohol (see WARNINGS and PRECAUTIONS: Pediatric Use). WARNINGS: PAVULON® SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSES BY OR UNDER THE SUPERVISION OF EXPERIENCED CLINICIANS WHO ARE FAMILIAR WITH ITS ACTIONS AND THE POSSIBLE COMPLICATIONS THAT MIGHT OCCUR FOLLOWING ITS USE. THE DRUG SHOULD NOT BE ADMINISTERED UNLESS FACILITIES FOR INTUBATION, ARTIFICIAL RESPIRATION, OXYGEN THERAPY, AND REVERSAL AGENTS ARE IMMEDIATELY AVAILABLE. THE CLINICIAN MUST BE PREPARED TO ASSIST OR CONTROL RESPIRATION. Anaphylaxis: Severe anaphylactic reactions to neuromuscular blocking agents, including Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PAVULON®, have been reported. These reactions have, in some cases, been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents, since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported. In patients who are known to have myasthenia gravis or the myasthenic (Eaton-Lambert) syndrome, small doses of PAVULON® may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants. PAVULON® contains benzyl alcohol, which is potentially toxic when administered locally to neural tissue. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see WARNINGS and PRECAUTIONS: Pediatric Use). PRECAUTIONS: USE OF A PERIPHERAL NERVE STIMULATOR WILL USUALLY BE OF VALUE FOR MONITORING OF NEUROMUSCULAR BLOCKING EFFECT, AVOIDING OVERDOSAGE AND ASSISTING IN EVALUATION OF RECOVERY. Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda General: Although PAVULON® has been used successfully in many patients with pre-existing pulmonary, hepatic, or renal disease, caution should be exercised in these situations. Anaphylaxis: Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. In addition, inform your patients that severe anaphylactic reactions to neuromuscular blocking agents, including PAVULON®, have been reported. Renal Failure: A major portion of pancuronium, as well as an active metabolite, are recovered in urine. The elimination half-life is doubled and the plasma clearance is reduced in patients with renal failure; at the same time, the rate of recovery of neuromuscular blockade is variable and sometimes very much slower than normal (see Pharmacokinetics). This information should be taken into consideration if pancuronium is selected, for other reasons, to be used in a patient with renal failure. Altered Circulation Time: Conditions associated with slower circulation time in cardiovascular disease, old age, edematous states resulting in increased volume of distribution may contribute to a delay in onset time; therefore, dosage should not be increased. Hepatic and/or Biliary Tract Disease: The doubled elimination half-life and reduced plasma clearance determined in patients with hepatic and/or biliary tract disease, as well as limited data showing that recovery time is prolonged an average of 65% in patients with biliary tract obstruction, suggests that prolongation of neuromuscular blockade may occur. At the same time, these conditions are characterized by an approximately 50% increase in volume of distribution of pancuronium, suggesting that the total initial dose to achieve adequate relaxation may in some cases be high. The possibility of slower onset, higher total dosage and prolongation of neuromuscular blockade must be taken into consideration when pancuronium is used in these patients (see also Pharmacokinetics). Long-term Use in I.C.U.: In the intensive care unit, in rare cases, long-term use of neuromuscular blocking drugs to facilitate mechanical ventilation may be associated with prolonged paralysis and/or skeletal muscle weakness, that may be first noted during attempts to wean such patients from the ventilator. Typically, such patients receive other drugs such as broad spectrum antibiotics, Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda narcotics and/or steroids and may have electrolyte imbalance and diseases which lead to electrolyte imbalance, hypoxic episodes of varying duration, acid-base imbalance and extreme debilitation, any of which may enhance the actions of a neuromuscular blocking agent. Additionally, patients immobilized for extended periods frequently develop symptoms consistent with disuse muscle atrophy. Therefore, when there is a need for long-term mechanical ventilation, the benefits to-risk ratio of neuromuscular blockade must be considered. Continuous infusion or intermittent bolus dosing to support mechanical ventilation, has not been studied sufficiently to support dosage recommendations. UNDER THE ABOVE CONDITIONS, APPROPRIATE MONITORING, SUCH AS USE OF A PERIPHERAL NERVE STIMULATOR, TO ASSESS THE DEGREE OF NEUROMUSCULAR BLOCKADE, MAY PRECLUDE INADVERTANT EXCESS DOSING. Severe Obesity or Neuromuscular Disease: Patients with severe obesity or neuromuscular disease may pose airway and/or ventilatory problems requiring special care before, during and after the use of neuromuscular blocking agents such as PAVULON®. C.N.S.: PAVULON® has no known effect on consciousness, the pain threshold or cerebration. Administration should be accompanied by adequate anesthesia or sedation. Drug Interactions: Prior administration of succinylcholine may enhance the neuromuscular blocking effect of PAVULON® and increase its duration of action. If succinylcholine is used before PAVULON® the administration of PAVULON® should be delayed until the patient starts recovering from succinylcholine-induced neuromuscular blockade. If a small dose of PAVULON® is given at least 3 minutes prior to the administration of succinylcholine, in order to reduce the incidence and intensity of succinylcholine-induced fasciculations, this dose may induce a degree of neuromuscular block sufficient to cause respiratory depression in some patients. Other nondepolarizing neuromuscular blocking agents (vecuronium, atracurium, d-tubocurarine, metocurine, and gallamine) behave in a clinically similar fashion to PAVULON®. The combinations of PAVULON®-metocurine and PAVULON®-d-tubocurarine are significantly more potent than the Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda additive effects of each of the individual drugs given alone; however, the duration of blockade of these combinations is not prolonged. There are insufficient data to support concomitant use of pancuronium and the other three above mentioned muscle relaxants in the same patients. Inhalational Anesthetics: Use of volatile inhalational anesthetics such as enflurane, isoflurane, and halothane with PAVULON® will enhance neuromuscular blockade. Potentiation is most prominent with use of enflurane and isoflurane. With the above agents, the intubating dose of PAVULON® may be the same as with balanced anesthesia unless the inhalational anesthetic has been administered for a sufficient time at a sufficient dose to have reached clinical equilibrium. The relatively long duration of action of pancuronium should be taken into consideration when the drug is selected for intubation in these circumstances. Clinical experience and animal experiments suggest that pancuronium should be given with caution to patients receiving chronic tricyclic antidepressant therapy who are anesthetized with halothane because severe ventricular arrhythmias may result from this combination. The severity of the arrhythmias appears in part related to the dose of pancuronium. Antibiotics: Parenteral/intraperitoneal administration of high doses of certain antibiotics may intensify or produce neuromuscular block on their own. The following antibiotics have been associated with various degrees of paralysis: aminoglycosides (such as neomycin, streptomycin, kanamycin, gentamicin, and dihydrostreptomycin); tetracyclines; bacitracin; polymyxin B; colistin; and sodium colistimethate. If these or other newly introduced antibiotics are used preoperatively or in conjunction with PAVULON®, unexpected prolongation of neuromuscular block should be considered a possibility. Other: Experience concerning injection of quinidine during recovery from use of other muscle relaxants suggests that recurrent paralysis may occur. This possibility must also be considered for PAVULON® (pancuronium bromide) injection. Electrolyte imbalance and diseases which lead to electrolyte imbalance, such as adrenal cortical insufficiency, have been shown to alter neuromuscular blockade. Depending on the nature of the Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda imbalance, either enhancement or inhibition may be expected. Magnesium salts, administered for the management of toxemia of pregnancy, may enhance the neuromuscular blockade. Drug/laboratory test interactions: None known. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential or impairment of fertility. Pregnancy: Pregnancy Category C: Animal reproduction studies have not been performed. It is not known whether PAVULON® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PAVULON® should be given to a pregnant woman only if the administering clinician decides that the benefits outweigh the risks. PAVULON® may be used in operative obstetrics (Cesarean section), but reversal of pancuronium may be unsatisfactory in patients receiving magnesium sulfate for toxemia of pregnancy, because magnesium salts enhance neuromuscular blockade. Dosage should usually be reduced, as indicated, in such cases. It is also recommended that the interval between use of pancuronium and delivery be reasonably short to avoid clinically significant placental transfer. Pediatric Use: Dose response studies in children indicate that, with the exception of neonates, dosage requirements are the same as for adults. Due to the potential toxicity of benzyl alcohol in neonates, solutions containing benzyl alcohol must not be used in this patient population (see CONTRAINDICATIONS). This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. ADVERSE REACTIONS: Neuromuscular: The most frequent adverse reaction to nondepolarizing blocking agents as a class consists of an extension of drug’s pharmacological action beyond the time period needed. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiratory insufficiency or apnea. Inadequate reversal of the neuromuscular blockade is possible with PAVULON® as with all curariform drugs. These adverse experiences are managed by manual or mechanical ventilation until recovery is judged adequate. Prolonged paralysis and/or skeletal muscle weakness have been reported after long-term use to support mechanical ventilation in the intensive care unit. Cardiovascular: See discussion of circulatory effects in CLINICAL PHARMACOLOGY. Gastrointestinal: Salivation is sometimes noted during very light anesthesia, especially if no anticholinergic premedication is used. Skin: An occasional transient rash is noted accompanying the use of PAVULON®. Other: Although histamine release is not a characteristic action of PAVULON®, rare hypersensitivity reactions such as bronchospasm, flushing, redness, hypotension, tachycardia, and other reactions possibly mediated by histamine release have been reported. Post-Marketing: There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with the use of neuromuscular blocking agents, including PAVULON®. These reactions, in some cases, have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see WARNINGS and PRECAUTIONS). Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE: The possibility of iatrogenic overdosage can be minimized by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Excessive doses of PAVULON® produce enhanced pharmacological effects. Residual neuromuscular blockade beyond the time period needed may occur with PAVULON® as with other neuromuscular blockers. This may be manifested by skeletal muscle weakness, decreased respiratory reserve, low tidal volume, or apnea. A peripheral nerve stimulator may be used to assess the degree of residual neuromuscular blockade and help to differentiate residual neuromuscular blockade from other causes of decreased respiratory reserve. Regonol® (pyridostigmine bromide) injection, neostigmine, or edrophonium, in conjunction with atropine or glycopyrrolate, will usually antagonize the skeletal muscle relaxant action of PAVULON®. Satisfactory reversal can be judged by adequacy of skeletal muscle tone and by adequacy of respiration. A peripheral nerve stimulator may also be used to monitor restoration of twitch response. Failure of prompt reversal (within 30 minutes) may occur in the presence of extreme debilitation, carcinomatosis, and with concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or cause respiratory depression of their own. Under such circumstances, the management is the same as that of prolonged neuromuscular blockade. Ventilation must be supported by artificial means until the patient has resumed control of his respiration. Prior to the use of reversal agents, reference should be made to the specific package insert of the reversal agent. DOSAGE AND ADMINISTRATION: NOTE: CONTAINS BENZYL ALCOHOL (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS: Pediatric Use) PAVULON® (pancuronium bromide) injection is for intravenous use only. This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. DOSAGE MUST BE INDIVIDUALIZED IN EACH CASE. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only. Since potent inhalational anesthetics or prior use of Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda succinylcholine may enhance the intensity and duration of PAVULON® (see PRECAUTIONS: Drug Interactions), the lower end of the recommended initial dosage range may suffice when PAVULON® is first used after intubation with succinylcholine and/or after maintenance doses of volatile liquid inhalational anesthetics are started. To obtain maximum clinical benefits of PAVULON® and to minimize the possibility of overdosage, the monitoring of muscle twitch response to a peripheral nerve stimulator is advised. In adults under balanced anesthesia the initial intravenous dosage range is 0.04 to 0.1 mg/kg. Later incremental doses starting at 0.01 mg/kg may be used. These increments slightly increase the magnitude of the blockade and significantly increase the duration of blockade, because a significant number of myoneural junctions are still blocked when there is clinical need for more drug. If PAVULON® is used to provide skeletal muscle relaxation for endotracheal intubation, a bolus dose of 0.06 to 0.1 mg/kg are recommended. Conditions satisfactory in intubation are usually present within 2 to 3 minutes. (see PRECAUTIONS). Dosage in Children: Dose response studies in children indicate that, with the exception of neonates, dosage requirements are the same as for adults. Due to the potential toxicity of benzyl alcohol in neonates, solutions containing benzyl alcohol must not be used in this patient population (see CONTRAINDICATIONS). Cesarean Section: The dosage to provide relaxation for intubation and operation is the same as for general surgical procedures. The dosage to provide relaxation, following usage of succinylcholine for intubation (see PRECAUTIONS: Drug Interactions), is the same as for general surgical procedures. Compatibility: PAVULON® is compatible in solution with: 0.9% sodium chloride injection 5% dextrose and sodium chloride injection 5% dextrose injection Lactated Ringer’s injection Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When mixed with the above solutions in glass or plastic containers, PAVULON® will remain stable in Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda solution for 48 hours with no alteration in potency or pH; no decomposition is observed and there is no absorption to either the glass or plastic container. HOW SUPPLIED: PAVULON® is packaged in the following forms: 2 mL ampuls — 2 mg/mL — boxes of 25, NDC#0052-0444-26; 5 mL ampuls — 2 mg/mL — boxes of 25, NDC#0052-0444-25; 10 mL vials — 1 mg/mL — boxes of 25, NDC#0052-0443-25. STORAGE: Both concentrations of PAVULON® will maintain full clinical potency for six months if kept at a room temperature of 18° to 22°C (65° to 72°F); or for 3 years when refrigerated at 2° to 8°C (36° to 46°F). CAUTION: Federal law prohibits dispensing without prescription. company logo ORGANON INC. · WEST ORANGE, NEW JERSEY 07052 XXXXXXX Month/Year Reference ID: 2868556 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:06.519893	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017015s023lbl.pdf', 'application_number': 17015, 'submission_type': 'SUPPL ', 'submission_number': 23}
10,949	c o mp an y logo 4 HEPARIN SODIUM 5 INJECTION, USP 6 Rx only 7 8 DERIVED FROM PORCINE INTESTINAL MUCOSA. 9 Available as: Preservative Free or Contains Benzyl Alcohol or Parabens 10 DESCRIPTION: 11 Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called 12 glycosaminoglycans, having anticoagulant properties. Although others may be present, the 13 main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2 14 sulfamino-α-D-glucose 6-sulfate, (3) ß-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D 15 glucose and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually 16 in the order (2)> (1)> (4)> (3)> (5), and are joined by glycosidic linkages, forming polymers 17 of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate 18 and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are 19 partially replaced by sodium ions. 20 Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from 21 porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. It is 22 to be administered by intravenous or deep subcutaneous routes. The potency is determined 23 by a biological assay using a USP reference standard based on units of heparin activity per 24 milligram. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Structure of Heparin Sodium (representative subunits): structural formula 2 3 4 Heparin Sodium Injection, USP (porcine), preservative free, is available as follows: 5 Each mL of the 1,000 Units per mL preparation contains: 1,000 USP Heparin Units 6 (porcine); 9 mg sodium chloride; Water for Injection q.s. Made isotonic with sodium 7 chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH 8 adjustment (5.0-7.5). 9 Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available 10 as follows: 11 Each mL of the 5,000 Units per mL preparation contains: 5,000 USP Heparin Units 12 (porcine); 6 mg sodium chloride; 15 mg benzyl alcohol (as a preservative); Water for 13 Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH 14 adjustment (5.0-7.5). 15 Heparin Sodium Injection, USP (porcine), preserved with parabens, is available as 16 follows: 17 Each mL of the 1,000 Units per mL preparation contains: 1,000 USP Heparin Units 18 (porcine); 9 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for 19 Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium 20 hydroxide may have been added for pH adjustment (5.0-7.5). 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Each mL of the 5,000 Units per mL preparation contains: 5,000 USP Heparin Units 2 (porcine); 5 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for 3 Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium 4 hydroxide may have been added for pH adjustment (5.0-7.5). 5 Each mL of the 10,000 Units per mL preparation contains: 10,000 USP Heparin Units 6 (porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. 7 Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 8 7.5). 9 Each mL of the 20,000 Units per mL preparation contains: 20,000 USP Heparin Units 10 (porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s. 11 Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0 12 7.5). 13 CLINICAL PHARMACOLOGY: 14 Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots 15 both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. 16 Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit 17 thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin 18 to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit 19 further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to 20 fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation 21 of the fibrin stabilizing factor. 22 Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full 23 therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 heparin. 2 Patients over 60 years of age, following similar doses of heparin, may have higher 3 plasma levels of heparin and longer activated partial thromboplastin times (APTTs) 4 compared with patients under 60 years of age. 5 Peak plasma levels of heparin are achieved two to four hours following subcutaneous 6 administration, although there are considerable individual variations. Loglinear plots of 7 heparin plasma concentrations with time, for a wide range of dose levels, are linear, which 8 suggests the absence of zero order processes. Liver and the reticuloendothelial system are 9 the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha 10 phase (t1⁄2 = 10 minutes) and after the age of 40 a slower beta phase, indicates uptake in 11 organs. The absence of a relationship between anticoagulant half-life and concentration half 12 life may reflect factors such as protein binding of heparin. 13 Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. 14 INDICATIONS AND USAGE: 15 Heparin Sodium Injection is indicated for: 16 Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its 17 extension; 18 Low-dose regimen for prevention of postoperative deep venous thrombosis and 19 pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for 20 other reasons, are at risk of developing thromboembolic disease (see DOSAGE AND 21 ADMINISTRATION); 22 Prophylaxis and treatment of pulmonary embolism; 23 Atrial fibrillation with embolization; 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Diagnosis and treatment of acute and chronic consumptive coagulopathies 2 (disseminated intravascular coagulation); 3 Prevention of clotting in arterial and cardiac surgery; 4 Prophylaxis and treatment of peripheral arterial embolism. 5 Heparin may also be employed as an anticoagulant in blood transfusions, 6 extracorporeal circulation, and dialysis procedures and in blood samples for laboratory 7 purposes. 8 CONTRAINDICATIONS: 9 Heparin sodium should NOT be used in patients with the following conditions: 10 Severe thrombocytopenia; 11 When suitable blood coagulation tests, e.g., the whole blood clotting time, partial 12 thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication 13 refers to full-dose heparin; there is usually no need to monitor coagulation parameters in 14 patients receiving low-dose heparin); 15 An uncontrollable active bleeding state (see WARNINGS), except when this is due 16 to disseminated intravascular coagulation. 17 Pregnancy, Nursing Mothers, and Pediatric Use 18 Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol 19 to neonates, infants, pregnant women, or nursing mothers (see PRECAUTIONS, 20 Pregnancy, Nursing Mothers, and Pediatric Use). Benzyl alcohol has been associated with 21 serious adverse events and death, particularly in pediatric patients. Heparin Sodium 22 Injection, USP (porcine), preservative free, when indicated, should be used in these 23 populations. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 WARNINGS: 2 Heparin is not intended for intramuscular use. 3 Fatal Medication Errors 4 Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium 5 Injection is supplied in vials containing various strengths of heparin, including vials that 6 contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have 7 occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium 8 Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all 9 Heparin Sodium Injection vials to confirm the correct vial choice prior to administration of 10 the drug. 11 Hypersensitivity 12 Patients with documented hypersensitivity to heparin should be given the drug only in clearly 13 life-threatening situations (see ADVERSE REACTIONS, Hypersensitivity). 14 Hemorrhage 15 Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall 16 in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious 17 consideration of a hemorrhagic event. 18 Heparin sodium should be used with extreme caution in disease states in which there 19 is increased danger of hemorrhage. Some of the conditions in which increased danger of 20 hemorrhage exists are: 21 22 Cardiovascular—Subacute bacterial endocarditis, severe hypertension. 23 24 Surgical—During and immediately following (a) spinal tap or spinal anesthesia or (b) major 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 10 15 20 25 7 1 surgery, especially involving the brain, spinal cord, or eye. 2 3 Hematologic—Conditions associated with increased bleeding tendencies, such as 4 hemophilia, thrombocytopenia and some vascular purpuras. 6 Gastrointestinal—Ulcerative lesions and continuous tube drainage of the stomach or small 7 intestine. 8 9 Other—Menstruation, liver disease with impaired hemostasis. Coagulation Testing 11 When heparin sodium is administered in therapeutic amounts, its dosage should be regulated 12 by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if 13 hemorrhage occurs, heparin sodium should be promptly discontinued (see 14 OVERDOSAGE). Thrombocytopenia 16 Thrombocytopenia has been reported to occur in patients receiving heparin with a reported 17 incidence of up to 30%. Platelet counts should be obtained at baseline and periodically 18 during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) 19 may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent 21 thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced 22 Thrombocytopenia and Thrombosis), the heparin product should be discontinued, and, if 23 necessary, an alternative anticoagulant administered. 24 Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction 2 resulting from irreversible aggregation of platelets. HIT may progress to the 3 development of venous and arterial thromboses, a condition referred to as Heparin- 4 induced Thrombocytopenia and Thrombosis (HITT). Thrombotic events may also be 5 the initial presentation for HITT. These serious thromboembolic events include deep 6 vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, 7 myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, 8 gangrene of the extremities that may lead to amputation, and possibly death. 9 Thrombocytopenia of any degree should be monitored closely. If the platelet count falls 10 below 100,000/mm 3 or if recurrent thrombosis develops, the heparin product should be 11 promptly discontinued and alternative anticoagulants considered, if patients require 12 continued anticoagulation. 13 Delayed Onset of HIT and HITT 14 Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and 15 Thrombosis can occur up to several weeks after the discontinuation of heparin therapy. 16 Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin 17 should be evaluated for HIT and HITT. 18 PRECAUTIONS: 19 General 20 Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced 21 Thrombocytopenia and Thrombosis (HITT) 22 See WARNINGS. 23 Heparin Resistance—Increased resistance to heparin is frequently encountered in fever, 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 10 15 20 25 9 1 thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, 2 cancer and in postsurgical patients. 3 4 Increased Risk to Older Patients, Especially Women—A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. 6 Laboratory Tests 7 Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended 8 during the entire course of heparin therapy, regardless of the route of administration (see 9 DOSAGE AND ADMINISTRATION). Drug Interactions 11 Oral Anticoagulants—Heparin sodium may prolong the one-stage prothrombin time. 12 Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at 13 least five hours after the last intravenous dose or 24 hours after the last subcutaneous dose 14 should elapse before blood is drawn, if a valid prothrombin time is to be obtained. 16 Platelet Inhibitors—Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, 17 indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet- 18 aggregation reactions (the main hemostatic defense of heparinized patients) may induce 19 bleeding and should be used with caution in patients receiving heparin sodium. 21 Other Interactions—Digitalis, tetracyclines, nicotine or antihistamines may partially 22 counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin 23 administered to heparinized patients may result in a decrease of the partial thromboplastin 24 time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are 26 recommended during coadministration of heparin and intravenous nitroglycerin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Drug/Laboratory Tests Interactions 2 Hyperaminotransferasemia—Significant elevations of aminotransferase (SGOT [S-AST] and 3 SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) 4 who have received heparin. Since aminotransferase determinations are important in the 5 differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases 6 that might be caused by drugs (like heparin) should be interpreted with caution. 7 Carcinogenesis, Mutagenesis, Impairment of Fertility 8 No long-term studies in animals have been performed to evaluate carcinogenic potential of 9 heparin. Also, no reproduction studies in animals have been performed concerning 10 mutagenesis or impairment of fertility. 11 Pregnancy 12 Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, 13 to pregnant women (see CONTRAINDICATIONS, Pregnancy, Nursing Mothers, and 14 Pediatric Use and PRECAUTIONS, Pediatric Use). Heparin Sodium Injection, USP 15 (porcine), preservative free, when indicated, should be administered to pregnant women. 16 17 Teratogenic Effects: Pregnancy Category C— 18 Animal reproduction studies have not been conducted with heparin sodium. It is also not 19 known whether heparin sodium can cause fetal harm when administered to a pregnant 20 woman or can affect reproduction capacity. Heparin sodium should be given to a pregnant 21 woman only if clearly needed. 22 23 Nonteratogenic Effects—Heparin does not cross the placental barrier. 24 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Nursing Mothers Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, to nursing mothers (see CONTRAINDICATIONS, Pregnancy, Nursing Mothers, and Pediatric Use and PRECAUTIONS, Pediatric Use). Heparin Sodium Injection, USP (porcine), preservative free, when indicated, should be administered to nursing mothers. Heparin is not excreted in human milk. Pediatric Use See DOSAGE AND ADMINISTRATION, Pediatric Use. Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, to neonates and infants (see CONTRAINDICATIONS, Pregnancy, Nursing Mothers, and Pediatric Use). Heparin Sodium Injection, USP (porcine), preservative free, when indicated, should be administered to neonates and infants. Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99mg/kg/day in neonates and low-birthweight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 1 to develop toxicity. Practitioners administering this and other medications containing benzyl 2 alcohol should consider the combined daily metabolic load of benzyl alcohol from all 3 sources. 4 Geriatric Use 5 A higher incidence of bleeding has been reported in patients over 60 years of age, especially 6 women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of 7 heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and 8 DOSAGE AND ADMINISTRATION). 9 ADVERSE REACTIONS: 10 Hemorrhage 11 Hemorrhage is the chief complication that may result from heparin therapy (see 12 WARNINGS). An overly prolonged clotting time or minor bleeding during therapy can 13 usually be controlled by withdrawing the drug (see OVERDOSAGE). It should be 14 appreciated that gastrointestinal or urinary tract bleeding during anticoagulant 15 therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at 16 any site but certain specific hemorrhagic complications may be difficult to detect: 17 (a) Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during 18 anticoagulant therapy. Therefore, such treatment should be discontinued in patients who 19 develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of 20 corrective therapy should not depend on laboratory confirmation of the diagnosis, since any 21 delay in an acute situation may result in the patient’s death. 22 (b) Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive 23 age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 may be fatal. (c) Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT See WARNINGS. Local Irritation Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended. Hypersensitivity Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur (see WARNINGS and PRECAUTIONS). Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated complications, remains to be determined. Miscellaneous Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) 2 levels have occurred in a high percentage of patients (and healthy subjects) who have 3 received heparin. 4 OVERDOSAGE: 5 Symptoms 6 Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools 7 may be noted as the first sign of bleeding. Easy bruising or petechial formations may 8 precede frank bleeding. 9 Treatment 10 Neutralization of Heparin Effect—When clinical circumstances (bleeding) require reversal of 11 heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin 12 sodium. No more than 50 mg should be administered, very slowly, in any 10 minute 13 period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The 14 amount of protamine required decreases over time as heparin is metabolized. Although the 15 metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be 16 assumed to have a half-life of about 1/2 hour after intravenous injection. 17 Administration of protamine sulfate can cause severe hypotensive and anaphylactoid 18 reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug 19 should be given only when resuscitation techniques and treatment of anaphylactoid shock are 20 readily available. 21 For additional information consult the labeling of Protamine Sulfate Injection, USP 22 products. 23 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE AND ADMINISTRATION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Slight discoloration does not alter potency. Confirm the choice of the correct Heparin Sodium Injection vial prior to administration of the drug to a patient (see WARNINGS, Fatal Medication Errors). The 1 mL vial must not be confused with a “catheter lock flush” vial or other 1 mL vial of inappropriate strength. Confirm that you have selected the correct medication and strength prior to administration of the drug. When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site. The dosage of heparin sodium should be adjusted according to the patient’s coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every four hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn four to six hours after the injection. Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. Converting to Oral Anticoagulant When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time. In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering. Therapeutic Anticoagulant Effect With Full-Dose Heparin Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 METHOD OF RECOMMENDED ADMINISTRATION FREQUENCY DOSE (based on 150 lb [68 kg] patient) Deep Subcutaneous (Intrafat) Injection A different site should be used for each injection to prevent the development of massive hematoma Initial Dose Every 8 hours or Every 12 hours 5,000 units by IV injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose Every 4 to 6 hours Intravenous Infusion Initial Dose Continuous 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP 5,000 units by IV injection 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Pediatric Use Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, to neonates and infants (see CONTRAINDICATIONS, Pregnancy, Nursing Mothers, and Pediatric Use and PRECAUTIONS, Pediatric Use). When indicated, Heparin Sodium Injection, USP (porcine), preservative free should be used in neonates and infants. Follow recommendations of appropriate pediatric reference texts. In general, the following dosage schedule may be used as a guideline: Initial Dose: 50 units/kg (IV, infusion) Maintenance Dose: 100 units/kg (IV, infusion) every four hours, or 20,000 units/m2/24 hours continuously Geriatric Use Patients over 60 years of age may require lower doses of heparin. Surgery of the Heart and Blood Vessels Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units of heparin sodium per kilogram of body weight is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. Low-Dose Prophylaxis of Postoperative Thromboembolism A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism. The most widely used dosage has been 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery. Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation test values should be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters. Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. Blood Transfusion Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of 2 whole blood. 3 Laboratory Samples 4 Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is 5 usually employed to prevent coagulation of the sample. Leukocyte counts should be 6 performed on heparinized blood within two hours after addition of the heparin. Heparinized 7 blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or 8 platelet counts. 9 HOW SUPPLIED: 10 Heparin Sodium Injection, USP (porcine), preservative free, is available as follows: Product NDC No. No. 27602 63323-276-02 1,000 USP Heparin Units/mL, 2 mL fill in a 2 mL single dose, flip-top vial, in packages of 25. 11 12 Preservative Free 13 Discard Unused Portion. 14 Do not use if solution is discolored or contains a precipitate. 15 16 Heparin Sodium Injection, USP (porcine) contains benzyl alcohol and is available as 17 follows: Product NDC No. No. 4710 63323-047-10 5,000 USP Heparin Units/mL, 10 mL fill in a 10 mL multiple dose, flip-top vial, in packages of 25. 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 Use only if solution is clear and seal intact. 3 4 Heparin Sodium Injection, USP (porcine) contains parabens and is available as follows: Product NDC No. No. 504001* 63323-540-01 504011 63323-540-11 504031 63323-540-31 926201** 63323-262-01 504201* 63323-542-01 504207 63323-542-07 915501** 63323-915-01 5 6 Packaged in a plastic or glass vial. 7 *Packaged in a plastic vial. 1,000 USP Heparin Units/mL, 1 mL fill in a 3 mL vial. 1,000 USP Heparin Units/mL, 10 mL fill in a 10 mL vial. 1,000 USP Heparin Units/mL, 30 mL fill in a 30 mL vial. 5,000 USP Heparin Units/mL, 1 mL fill in a 3 mL vial. 10,000 USP Heparin Units/mL, 1 mL fill in a 3 mL vial. 10,000 USP Heparin Units/mL, 5 mL fill in a 6 mL vial. 20,000 USP Heparin Units/mL, 1 mL fill in a 3 mL vial. 8 The above products are available in multiple dose, flip-top vials packaged in 25. 9 Do not use if solution is discolored or contains a precipitate. 10 STORAGE: 11 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. 12 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c o m pan y l ogo 1 REFERENCES: 2 1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced 3 Thrombocytopenia – A Case Report – J Jpn Assn Torca Surg. 1992;40(3):110-111. 4 2. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and 5 Thrombosis. Annals of Internal Medicine. 2001;135:502-506. 6 3. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced 7 Thrombocytopenia. Annals of Internal Medicine, 2002;136:210-215. 8 4. Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative 9 for Heparin-Induced Thrombosis.” Chest 98(1524-26). 10 5. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. 11 Annals of Emergency Medicine, 2005;45(4):417-419. 12 6. Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced 13 Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post- 14 Angiography Pulmonary Embolism. Blood. 2003;102(11):127b. 15 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:06.637461	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017029s120,017651s048lbl.pdf', 'application_number': 17029, 'submission_type': 'SUPPL ', 'submission_number': 120}
10,950	NDA 17-037/S-154/S-1565/S-156 Page 3 HEP-LOCK U/P Preservative-Free (Heparin Lock Flush Solution, USP) Rx only DESCRIPTION Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6- sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)>(1)>(4)>(3)>(5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. Structural formula of Heparin Sodium (representative sub-units): HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP) is a sterile solution for intravenous flush only. It is not to be used for anticoagulant therapy. HEP-LOCK U/P is specially formulated for use in situations where the use of preservatives is not advisable. Each mL contains heparin sodium 10 or 100 USP units, derived from porcine intestines and standardized for use as an anticoagulant, sodium chloride 8 mg, monobasic sodium phosphate monohydrate 2.3 mg, and dibasic sodium phosphate anhydrous 0.5 mg in Water for Injection. pH 5.0 -7.5. The potency is determined by biological assay using a USP reference standard based on units of heparin activity per milligram. CLINICAL PHARMACOLOGY Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin. Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear, which suggests the absence of zero order processes. Liver and the reticulo-endothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t1/2 = 10 min), and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-154/S-1565/S-156 Page 4 after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin. Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. INDICATIONS AND USAGE HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP) is intended to maintain patency of an indwelling venipuncture device designed for intermittent injection or infusion therapy or blood sampling. Heparin Lock Flush Solution may be used following initial placement of the device in the vein, after each injection of a medication or after withdrawal of blood for laboratory tests. (See DOSAGE AND ADMINISTRATION, Maintenance of Patency of Intravenous Devices for directions for use.) HEP-LOCK U/P is not to be used for anticoagulant therapy. CONTRAINDICATIONS Heparin sodium should NOT be used in patients with the following conditions: severe thrombocytopenia; an uncontrollable active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation. WARNINGS Heparin is not intended for intramuscular use. Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life- threatening situations. (See ADVERSE REACTIONS, Hypersensitivity.) Hemorrhage Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event. Heparin sodium should be used with extreme caution in infants and in patients with disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are: Cardiovascular Subacute bacterial endocarditis, severe hypertension. Surgical During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye. Hematologic Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Gastrointestinal Ulcerative lesions and continuous tube drainage of the stomach or small intestine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-154/S-1565/S-156 Page 5 Other Menstruation, liver disease with impaired hemostasis. Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30%. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops (see PRECAUTIONS, General–White Clot Syndrome), the heparin product should be discontinued. If continued heparin therapy is essential, administration of heparin from a different organ source can be reinstituted with caution. Use in Neonates and Infants The 100 unit/mL concentration should not be used in neonates or in infants who weigh less than 10 kg because of the risk of systemic anticoagulation. Caution is necessary when using the 10 unit/mL concentration in premature infants who weigh less than 1 kg who are receiving frequent flushes since a therapeutic heparin dose may be given to the infant in a 24-hour period. PRECAUTIONS General Precautions must be exercised when drugs that are incompatible with heparin are administered through an indwelling intravenous catheter containing Preservative-Free Heparin Lock Flush Solution. (See DOSAGE AND ADMINISTRATION, Maintenance of Patency of Intravenous Devices.) The concentration of phosphorus in the heparin solution is 0.63 mg/mL. White Clot Syndrome It has been reported that patients on heparin may develop new thrombus formation in association with thrombocytopenia resulting from irreversible aggregation of platelets induced by heparin, the so-called "white clot syndrome." The process may lead to severe thromboembolic complications like skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death. Therefore, heparin administration should be promptly discontinued if a patient develops new thrombosis in association with thrombocytopenia. Increased Risk to Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. Laboratory Tests Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin use (see DOSAGE AND ADMINISTRATION). Drug Interactions Platelet Inhibitors Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. Other Interactions Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-154/S-1565/S-156 Page 6 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of heparin sodium. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility. Pregnancy Teratogenic Effects—Pregnancy Category C Animal reproduction studies have not been conducted with heparin sodium. It is also not known whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Heparin sodium should be given to a pregnant woman only if clearly needed. Nonteratogenic Effects Heparin does not cross the placental barrier. Nursing Mothers Heparin is not excreted in human milk. Pediatric Use Safety and effectiveness in pediatric patients have not been established (see WARNINGS, Use in Neonates and Infants). Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see CLINICAL PHARMACOLOGY and PRECAUTIONS, General). ADVERSE REACTIONS Hemorrhage Hemorrhage is the chief complication that may result from heparin use (see WARNINGS, Hemorrhage). An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug (see OVERDOSAGE). Local Irritation Local irritation and erythema have been reported with the use of Heparin Lock Flush Solution. Hypersensitivity Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur. Thrombocytopenia has been reported to occur in patients receiving heparin, with a reported incidence of 0 to 30%. While often mild and of no obvious clinical significance, such thrombocytopenia can be accompanied by severe thromboembolic complications such as skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death. (See WARNINGS and PRECAUTIONS.) Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated complications remains to be determined. OVERDOSAGE Symptoms Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-154/S-1565/S-156 Page 7 Treatment—Neutralization of Heparin Effect When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP products. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Slight discoloration does not alter potency. Preservative-Free Heparin Lock Flush Solution in the 100 unit/mL concentration is not recommended for use in neonates and infants (see WARNINGS, Use In Neonates and Infants). Maintenance of Patency of Intravenous Devices To prevent clot formation in a heparin lock set or central venous catheter following its proper insertion, Preservative-Free Heparin Lock Flush Solution, USP is injected via the injection hub in a quantity sufficient to fill the entire device. This solution should be replaced each time the device is used. Aspirate before administering any solution via the device in order to confirm patency and location of needle or catheter tip. If the drug to be administered is incompatible with heparin, the entire device should be flushed with normal saline before and after the medication is administered; following the second saline flush, Preservative-Free Heparin Lock Flush Solution, USP may be reinstilled into the device. The device manufacturer's instructions should be consulted for specifics concerning its use. Usually this dilute heparin solution will maintain anticoagulation within the device for up to 4 hours. NOTE: Since repeated injections of small doses of heparin can alter tests for activated partial thromboplastin time (APTT), a baseline value for APTT should be obtained prior to insertion of an intravenous device. Withdrawal of Blood Samples Preservative-Free Heparin Lock Flush Solution, USP may also be used after each withdrawal of blood for laboratory tests. When heparin would interfere with or alter the results of blood tests, the heparin solution should be cleared from the device by aspirating and discarding it before withdrawing the blood sample. HOW SUPPLIED HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP) 10 USP units/mL 1 mL DOSETTE vials packaged in 25s (NDC 0641-0272-25) 100 USP units/mL 1 mL DOSETTE vials packaged in 25s (NDC 0641-0273-25) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-154/S-1565/S-156 Page 8 Storage Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. ESI LOGO, HEP-LOCK AND DOSETTE ARE REGISTERED TRADEMARKS OF BAXTER INTERNATIONAL INC., OR ITS SUBSIDIARIES. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-00090/3.0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:06.681244	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017037s154,055,156lbl.pdf', 'application_number': 17037, 'submission_type': 'SUPPL ', 'submission_number': 154}
10,952	Package Label Image 462-520-01 Label, Heparin Sodium Injection, USP, 5,000 units/mL, 10 mL Multiple Dose Vial Size: 1 1/8” x 2 7/8” USA Submission - 1 Corner: 1/8” 5/21/2009 PMS 151 PMS 1555 PMS 185 Black Bar Code: GS1 Data Bar (Limited 25/3) Multi-Color Pharmacode (67): Prints in PMS 151, 185 and Black. Guide Lines: DO NOT PRINT. Dotted Lines: Indicate Imprint Area. DO NOT PRINT. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Package Label Image 462-518-01 Label, Heparin Sodium Injection, USP, 1,000 units/mL, 10 mL Multiple Dose Vial Size: 1 1/8” x 2 7/8” USA Submission - 1 Corner: 1/8” 5/21/2009 PMS Purple PMS 257 PMS 185 Black Bar Code: GS1 Data Bar (Limited 25/3). Multi-Color Pharmacode (107): Prints in PMS Purple, PMS 185 and Black. Guide Lines: DO NOT PRINT. Dotted Lines: Indicate Imprint Area. DO NOT PRINT. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Package Label Image 462-516-01 Label, Heparin Sodium Injection, USP, 10,000 units/mL, 4 mL Multiple Dose Vial Size: 7/8” x 2 1/2” Corner: 1/8” USA Submission - 1 5/21/2009 PMS 4725 PMS 185 Black Bar Code: GS1 Data Bar (Stacked 25/2) Multi-Color Pharmacode (56): Prints in PMS 185 and Black. Guide Lines: DO NOT PRINT. Dotted Lines: Indicates Imprint Area. DO NOT PRINT. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda P a c k a g e Labe l Image 462-522-01 Label, Heparin Sodium Injection, USP, 1,000 units/mL, 30 mL Multiple Dose Vial Size: 1 1/2” x 3 1/2” Corner: 1/8” USA Submission - 1 5/21/2009 PMS Purple PMS 257 PMS 185 Black Bar Code: GS1 Data Bar (Limited 27/3) Multi-Color Pharmacode (175): Prints in PMS Purple, 185 and Black. Guide Lines: DO NOT PRINT. Dotted Lines: Indicate Imprint Area. DO NOT PRINT. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:06.891511	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017037s165lbl.pdf', 'application_number': 17037, 'submission_type': 'SUPPL ', 'submission_number': 165}
10,953	Heparin Sodium Injection, USP Rx only DESCRIPTION Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D glucose 6-sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose and (5) α-L iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)>(1)>(4)>(3)>(5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. Structural formula of Heparin Sodium (representative sub-units): structural formula Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Heparin Sodium Injection, USP is available in the following concentrations/mL: Heparin Sodium Sodium Chloride Benzyl Alcohol 1,000 USP units 8.6 mg 0.01 mL 5,000 USP units 7 mg 0.01 mL 10,000 USP units 5 mg 0.01 mL pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. Reference ID: 2909102 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin. Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age. Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, although there are considerable individual variations. Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear, which suggests the absence of zero order processes. Liver and the reticuloendothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t1/2 =10 min.) and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. INDICATIONS AND USAGE Heparin Sodium Injection is indicated for: Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension; Low-dose regimen for prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease (see DOSAGE AND ADMINISTRATION); Prophylaxis and treatment of pulmonary embolism; Atrial fibrillation with embolization; Reference ID: 2909102 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diagnosis and treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and cardiac surgery; Prophylaxis and treatment of peripheral arterial embolism. Heparin may also be employed as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures and in blood samples for laboratory purposes. CONTRAINDICATIONS Heparin sodium should NOT be used in patients with the following conditions: Severe thrombocytopenia; When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low- dose heparin); An uncontrolled active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation. WARNINGS Heparin is not intended for intramuscular use. Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection vials to confirm the correct vial choice prior to administration of the drug. Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. (See ADVERSE REACTIONS, Hypersensitivity.) Reference ID: 2909102 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemorrhage Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event. Heparin sodium should be used with extreme caution in disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are: Cardiovascular Subacute bacterial endocarditis, severe hypertension. Surgical During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Gastrointestinal Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other Menstruation, liver disease with impaired hemostasis. Coagulation Testing When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be promptly discontinued. (See OVERDOSAGE.) Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops Reference ID: 2909102 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (see Heparin-induced Thrombocytopenia (HIT) With or Without Thrombosis), the heparin product should be discontinued and, if necessary, an alternative anticoagulant administered. Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) HIT is a serious immune-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as HIT with thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and fatal outcomes. Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin sodium sources (including heparin flushes) should be discontinued and an alternative anticoagulant used. Future use of heparin sodium, especially within 3 to 6 months following the diagnosis of HIT (with or without thrombosis), and while patients test positive for HIT antibodies, should be avoided. Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin sodium, or platelet activation induced by heparin sodium. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin sodium in heparin sodium-naïve individuals, and reach a threshold by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours following heparin sodium initiation), especially in patients with a recent exposure to heparin sodium (i.e. previous 3 months). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation. Delayed Onset of HIT (With or Without Thrombosis) Heparin-induced Thrombocytopenia (with or without thrombosis) can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT (with or without thrombosis). Reference ID: 2909102 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use in Neonates This product contains the preservative benzyl alcohol and is not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials. (See WARNINGS, Fatal Medication Errors.) PRECAUTIONS General Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis.) See WARNINGS. Heparin Resistance Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. Increased Risk to Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. Laboratory Tests Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. (See DOSAGE AND ADMINISTRATION.) Drug Interactions Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous Reference ID: 2909102 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained. Platelet Inhibitors Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. Other Interactions Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin. Drug/Laboratory Tests Interactions Hyperaminotransferasemia Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases that might be caused by drugs (like heparin) should be interpreted with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility. Pregnancy Teratogenic Effects—Pregnancy Category C Animal reproduction studies have not been conducted with heparin sodium. It is also not known whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Heparin sodium should be given to a pregnant woman only if clearly needed. Reference ID: 2909102 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nonteratogenic Effects Heparin does not cross the placental barrier. Nursing Mothers Heparin is not excreted in human milk. Pediatric Use See DOSAGE AND ADMINISTRATION–Pediatric Use. Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Hemorrhage Hemorrhage is the chief complication that may result from heparin therapy. (See WARNINGS.) An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug. (See OVERDOSAGE.) It should be appreciated that gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect: a. Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient’s death. b. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized, may be fatal. c. Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis). See WARNINGS. Reference ID: 2909102 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Local Irritation Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended. Hypersensitivity Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur. (See Warnings, Precautions.) Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia- associated complications remains to be determined. Miscellaneous Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported. Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. OVERDOSAGE Symptoms Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. Treatment Neutralization of heparin effect. When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as Reference ID: 2909102 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP products. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Slight discoloration does not alter potency. Confirm the choice of the correct Heparin Sodium Injection vial prior to administration of the drug to a patient. (See WARNINGS, Fatal Medication Errors.) The 1 mL vial must not be confused with a “catheter lock flush” vial or other 1 mL vial of inappropriate strength. To lessen this risk, the 1 mL vial includes a red cautionary label that extends above the main label. Read the cautionary statement and confirm that you have selected the correct medication and strength. Then locate the “Tear Here” point on the label, and remove this red cautionary label prior to removing the flip-off cap. When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site. The dosage of heparin sodium should be adjusted according to the patient’s coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately Reference ID: 2909102 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.5 to 3 times the control value. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. Converting to Oral Anticoagulant When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about 5 hours after the last intravenous bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time. In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering. Therapeutic Anticoagulant Effect With Full-Dose Heparin Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: METHOD OF ADMINISTRATION Deep Subcutaneous (Intrafat) Injection FREQUENCY Initial dose RECOMMENDED DOSE [based on 150 lb (68 kg) patient] 5,000 units by IV injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for each injection to prevent the development of massive hematoma Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Reference ID: 2909102 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda METHOD OF ADMINISTRATION Intravenous Infusion FREQUENCY Initial dose RECOMMENDED DOSE [based on 150 lb (68 kg) patient] 5,000 units by IV injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion Pediatric Use Follow recommendations of appropriate pediatric reference texts. In general, the following dosage schedule may be used as a guideline: Initial Dose 50 units/kg (IV, drip) Maintenance Dose 100 units/kg (IV, drip) every 4 hours, or 20,000 units/m2/24 hours continuously Geriatric Use Patients over 60 years of age may require lower doses of heparin. Surgery of the Heart and Blood Vessels Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. Low-Dose Prophylaxis of Postoperative Thromboembolism A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism. The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25- to 26-gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery. Patients with bleeding disorders and those Reference ID: 2909102 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as should patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation test values should be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters. Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. Blood Transfusion Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood. Laboratory Samples Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within 2 hours after addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts. HOW SUPPLIED Heparin Sodium Injection, USP 1,000 USP units/mL 1 mL vial packaged in 25s (NDC 0641-0391-12) 10 mL Multiple Dose vial packaged in 25s (NDC 0641-2440-55) 30 mL Multiple Dose vial packaged in 25s (NDC 0641-2450-55) 5,000 USP units/mL Reference ID: 2909102 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 mL vial packaged in 25s (NDC 0641-0400-12) 10 mL Multiple Dose vial packaged in 25s (NDC 0641-2460-55) 10,000 USP units/mL 1 mL vial packaged in 25s (NDC 0641-0410-12) 4 mL Multiple Dose vial packaged in 25s (NDC 0641-2470-55) Storage Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. REFERENCES 1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia – A Case Report – J Jpn Assn Torca Surg.1992;40(3):110-111. 2. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of Internal Medicine. 2001;135:502-506. 3. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Internal Medicine, 2002;136:210-215. 4. Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative for Heparin-Induced Thrombosis.” Chest.1990;98:1524-26. 5. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency Medicine, 2005;45(4):417-419. 6. Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post- Angiography Pulmonary Embolism. Blood. 2003;102(11):127b. Baxter, Clear ID and the Diagonal Design are trademarks of Baxter International Inc. Patents Pending. company logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-01119, E Reference ID: 2909102 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:07.045437	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017037s168lbl.pdf', 'application_number': 17037, 'submission_type': 'SUPPL ', 'submission_number': 168}
10,954	Heparin Sodium Injection, USP Rx only DESCRIPTION Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) -L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino--D glucose 6-sulfate, (3) -D-glucuronic acid, (4) 2-acetamido-2-deoxy--D-glucose and (5) -L iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)(1)(4)(3)(5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. Structural formula of Heparin Sodium (representative sub-units): structural formula Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Heparin Sodium Injection, USP is available in the following concentrations/mL: Heparin Sodium Sodium Chloride Benzyl Alcohol 1,000 USP units 8.6 mg 0.01 mL 5,000 USP units 7 mg 0.01 mL 10,000 USP units 5 mg 0.01 mL pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. Reference ID: 3063479 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin. Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age. Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, although there are considerable individual variations. Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear, which suggests the absence of zero order processes. Liver and the reticuloendothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t1/2 10 min.) and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. INDICATIONS AND USAGE Heparin Sodium Injection is indicated for: Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension; Low-dose regimen for prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease (see DOSAGE AND ADMINISTRATION); Prophylaxis and treatment of pulmonary embolism; Atrial fibrillation with embolization; Reference ID: 3063479 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and cardiac surgery; Prophylaxis and treatment of peripheral arterial embolism. Heparin may also be employed as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures. CONTRAINDICATIONS Heparin sodium should NOT be used in patients with the following conditions: Severe thrombocytopenia; When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low- dose heparin); An uncontrolled active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation. WARNINGS Heparin is not intended for intramuscular use. Fatal Medication Errors Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin Sodium Injection vials to confirm the correct vial choice prior to administration of the drug. Benzyl Alcohol Toxicity Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. The minimum amount of benzyl alcohol at which toxicity may occur is not Reference ID: 3063479 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda known. Premature and low-birth weight infants may be more likely to develop toxicity (see PRECAUTIONS, Pediatric Use). Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. (See ADVERSE REACTIONS, Hypersensitivity.) Hemorrhage Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event. Heparin sodium should be used with extreme caution in disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are: Cardiovascular Subacute bacterial endocarditis, severe hypertension. Surgical During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Gastrointestinal Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other Menstruation, liver disease with impaired hemostasis. Coagulation Testing When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be promptly discontinued. (See OVERDOSAGE.) Reference ID: 3063479 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia (HIT) With or Without Thrombosis), the heparin product should be discontinued and, if necessary, an alternative anticoagulant administered. Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) HIT is a serious immune-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as HIT with thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and fatal outcomes. Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin sodium sources (including heparin flushes) should be discontinued and an alternative anticoagulant used. Future use of heparin sodium, especially within 3 to 6 months following the diagnosis of HIT (with or without thrombosis), and while patients test positive for HIT antibodies, should be avoided. Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin sodium, or platelet activation induced by heparin sodium. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin sodium in heparin sodium-naïve individuals, and reach a threshold by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours following heparin sodium initiation), especially in patients with a recent exposure to heparin sodium (i.e. previous 3 months). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation. Reference ID: 3063479 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Delayed Onset of HIT (With or Without Thrombosis) Heparin-induced Thrombocytopenia (with or without thrombosis) can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT (with or without thrombosis). Use in Neonates This product contains the preservative benzyl alcohol and is not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials. (See WARNINGS, Fatal Medication Errors.) PRECAUTIONS General Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis.) See WARNINGS. Heparin Resistance Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. Increased Risk to Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. Reference ID: 3063479 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. (See DOSAGE AND ADMINISTRATION.) Drug Interactions Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained. Platelet Inhibitors Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. Other Interactions Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin. Drug/Laboratory Tests Interactions Hyperaminotransferasemia Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases that might be caused by drugs (like heparin) should be interpreted with caution. Reference ID: 3063479 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility. Pregnancy Pregnancy Category C There are no adequate and well-controlled studies on heparin use in pregnant women. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans. Heparin sodium does not cross the placenta based on human and animal studies. Administration of heparin to pregnant animals at doses higher than the maximum human daily dose based on body weight resulted in increased resorptions. Use heparin sodium during pregnancy only if the potential benefit justifies the potential risk to the fetus. If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants (see PRECAUTIONS, Pediatric Use). In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 units/kg/day, approximately 10 times the maximum human daily dose based on body weight. The number of early resorptions increased in both species. There was no evidence of teratogenic effects. Nursing Mothers If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. Due to its large molecular weight, heparin is not to be excreted in human milk, and any heparin in milk would not be orally absorbed by a nursing infant. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Exercise caution when administering HEPARIN SODIUM INJECTION to a nursing mother (see PRECAUTIONS, Pediatric Use). Reference ID: 3063479 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience (see DOSAGE AND ADMINISTRATION, Pediatric Use). Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which HEPARIN SODIUM INJECTION vials have been confused with “catheter lock flush” vials (see WARNINGS, Fatal Medication Errors). Benzyl Alcohol Toxicity Use preservative-free Heparin Sodium Injection in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Hemorrhage Hemorrhage is the chief complication that may result from heparin therapy. (See WARNINGS.) An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by Reference ID: 3063479 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda withdrawing the drug. (See OVERDOSAGE.) It should be appreciated that gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect: a. Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient’s death. b. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized, may be fatal. c. Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis). See WARNINGS. Local Irritation Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended. Hypersensitivity Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur. (See WARNINGS and PRECAUTIONS.) Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia associated complications remains to be determined. Miscellaneous Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, Reference ID: 3063479 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported. Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. OVERDOSAGE Symptoms Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. Treatment Neutralization of heparin effect. When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1 solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP products. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Slight discoloration does not alter potency. Confirm the choice of the correct Heparin Sodium Injection vial prior to administration of the drug to a patient. (See WARNINGS, Fatal Medication Errors.) The 1 mL vial must not be confused with a “catheter lock flush” vial or other 1 mL vial of inappropriate strength. To lessen this risk, the 1 mL vial includes a red cautionary label that extends above the main label. Reference ID: 3063479 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Read the cautionary statement and confirm that you have selected the correct medication and strength. Then locate the “Tear Here” point on the label, and remove this red cautionary label prior to removing the flip-off cap. When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site. The dosage of heparin sodium should be adjusted according to the patient’s coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. Converting to Oral Anticoagulant When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about 5 hours after the last intravenous bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time. In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering. Reference ID: 3063479 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Therapeutic Anticoagulant Effect With Full-Dose Heparin Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: METHOD OF RECOMMENDED DOSE ADMINISTRATION FREQUENCY [based on 150 lb (68 kg) patient] Deep Subcutaneous Initial dose 5,000 units by IV injection, followed (Intrafat) Injection by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for Every 8 hours 8,000 to 10,000 units of a each injection to prevent the concentrated solution development of massive or hematoma Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9 Sodium Chloride Injection, USP Intravenous Infusion Every 4 to 6 hours Initial dose 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9 Sodium Chloride Injection, USP 5,000 units by IV injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9 Sodium Chloride Injection, USP (or in any compatible solution) for infusion Pediatric Use Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants (see WARNINGS, Benzyl Alcohol Toxicity and PRECAUTIONS, Pediatric Use). There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (IV bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Reference ID: 3063479 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 Geriatric Use Patients over 60 years of age may require lower doses of heparin. Surgery of the Heart and Blood Vessels Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. Low-Dose Prophylaxis of Postoperative Thromboembolism A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism. The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25- to 26-gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery. Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as should patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation test values should Reference ID: 3063479 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters. Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. Blood Transfusion Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9 Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9 Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood. Laboratory Samples Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within 2 hours after addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts. HOW SUPPLIED Heparin Sodium Injection, USP 1,000 USP units/mL 1 mL vial packaged in 25s (NDC 0641-0391-12) 30 mL Multiple Dose vial packaged in 25s (NDC 0641-2450-55) 5,000 USP units/mL 1 mL vial packaged in 25s (NDC 0641-0400-12) 10 mL Multiple Dose vial packaged in 25s (NDC 0641-2460-55) 10,000 USP units/mL 1 mL vial packaged in 25s (NDC 0641-0410-12) Storage Store at 20-25C (68-77F) See USP Controlled Room Temperature. Reference ID: 3063479 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For Product Inquiry call 1-877-845-0689. REFERENCES 1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia – A Case Report – J Jpn Assn Torca Surg.1992;40(3):110-111. 2. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of Internal Medicine. 2001;135:502-506. 3. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Internal Medicine, 2002;136:210-215. 4. Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative for Heparin-Induced Thrombosis.” Chest.1990;98:1524-26. 5. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency Medicine, 2005;45(4):417-419. 6. Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post- Angiography Pulmonary Embolism. Blood. 2003;102(11):127b. Manufactured by: company logo WEST-WARD PHARMACEUTICALS Eatontown, NJ 07724 USA Revised: September 2011 462-274-11 16 Reference ID: 3063479 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:07.158115	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017037s169.pdf', 'application_number': 17037, 'submission_type': 'SUPPL ', 'submission_number': 169}
10,951	NDA 17-037/S-158 Page 3 Heparin Sodium Injection, USP Rx only DESCRIPTION Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6- sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)>(1)>(4)>(3)>(5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. Structural formula of Heparin Sodium (representative sub-units): Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Heparin Sodium Injection, USP is available in the following concentrations/mL: Heparin Sodium Sodium Chloride Benzyl Alcohol 1000 USP units 8.6 mg 0.01 mL 5000 USP units 7 mg 0.01 mL 10,000 USP units 5 mg 0.01 mL pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. CLINICAL PHARMACOLOGY Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 4 Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age. Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, although there are considerable individual variations. Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear, which suggests the absence of zero order processes. Liver and the reticuloendothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t1/2 =10 min.) and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. INDICATIONS AND USAGE Heparin Sodium Injection is indicated for: Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension; Low-dose regimen for prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease (see DOSAGE AND ADMINISTRATION); Prophylaxis and treatment of pulmonary embolism; Atrial fibrillation with embolization; Diagnosis and treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and cardiac surgery; Prophylaxis and treatment of peripheral arterial embolism. Heparin may also be employed as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures and in blood samples for laboratory purposes. CONTRAINDICATIONS Heparin sodium should NOT be used in patients with the following conditions: Severe thrombocytopenia; When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin). An uncontrolled active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation. WARNINGS Heparin is not intended for intramuscular use. Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life- threatening situations. (See ADVERSE REACTIONS, Hypersensitivity.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 5 Hemorrhage Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event. Heparin sodium should be used with extreme caution in disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are: Cardiovascular Subacute bacterial endocarditis, severe hypertension. Surgical During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Gastrointestinal Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other Menstruation, liver disease with impaired hemostasis. Coagulation Testing When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be promptly discontinued. (See OVERDOSAGE.) Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30% up to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops (see Heparin- induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered. Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia Thrombosis (HITT) Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as Heparin-induced Thrombocytopenia and Thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered, if patients require continued anticoagulation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 6 Delayed Onset of HIT and HITT Heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT. Use in Neonates This product contains the preservative benzyl alcohol and is not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. PRECAUTIONS General Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT): see WARNINGS. Heparin Resistance Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. Increased Risk to Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. Laboratory Tests Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. (See DOSAGE AND ADMINISTRATION.) Drug Interactions Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained. Platelet Inhibitors Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. Other Interactions Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 7 nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin. Drug/Laboratory Tests Interactions Hyperaminotransferasemia Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases that might be caused by drugs (like heparin) should be interpreted with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility. Pregnancy Teratogenic Effects—Pregnancy Category C Animal reproduction studies have not been conducted with heparin sodium. It is also not known whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Heparin sodium should be given to a pregnant woman only if clearly needed. Nonteratogenic Effects Heparin does not cross the placental barrier. Nursing Mothers Heparin is not excreted in human milk. Pediatric Use See DOSAGE AND ADMINISTRATION–Pediatric Use. Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Hemorrhage Hemorrhage is the chief complication that may result from heparin therapy. (See WARNINGS.) An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug. (See OVERDOSAGE.) It should be appreciated that gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect: a. Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient’s death. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 8 b. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized, may be fatal. c. Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT: see WARNINGS. Local Irritation Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended. Hypersensitivity Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur. Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30%. While often mild and of no obvious clinical significance, such thrombocytopenia can be accompanied by severe thromboembolic complications such as skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death. (See WARNINGS and PRECAUTIONS.) Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated complications remains to be determined. Miscellaneous Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported. Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. OVERDOSAGE Symptoms Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. Treatment Neutralization of heparin effect. When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 9 Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP products. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Slight discoloration does not alter potency. When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution. Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site. The dosage of heparin sodium should be adjusted according to the patient’s coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. Converting to Oral Anticoagulant When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about 5 hours after the last intravenous bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time. In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 10 Therapeutic Anticoagulant Effect With Full-Dose Heparin Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE [based on 150 lb (68 kg) patient] Deep Subcutaneous (Intrafat) Injection Initial dose 5000 units by IV injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for each injection to prevent the development of massive hematoma Every 8 hours or 8000 to 10,000 units of a concentrated solution Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5000 units by IV injection Continuous 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion Pediatric Use Follow recommendations of appropriate pediatric reference texts. In general, the following dosage schedule may be used as a guideline: Initial Dose 50 units/kg (IV, drip) Maintenance Dose 100 units/kg (IV, drip) every 4 hours, or 20,000 units/m2/24 hours continuously Geriatric Use Patients over 60 years of age may require lower doses of heparin. Surgery of the Heart and Blood Vessels Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 11 Low-Dose Prophylaxis of Postoperative Thromboembolism A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism. The most widely used dosage has been 5000 units 2 hours before surgery and 5000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25- to 26-gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery. Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as should patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation test values should be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters. Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. Blood Transfusion Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood. Laboratory Samples Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within 2 hours after addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts. HOW SUPPLIED Heparin Sodium Injection, USP 1000 USP units/mL 1 mL DOSETTE vial packaged in 25s (NDC 0641-0391-25) 10 mL Multiple Dose vial packaged in 25s (NDC 0641-2440-45) 30 mL Multiple Dose vial packaged in 25s (NDC 0641-2450-45) 5000 USP units/mL 1 mL DOSETTE vial packaged in 25s (NDC 0641-0400-25) 10 mL Multiple Dose vial packaged in 25s (NDC 0641-2460-45) 10,000 USP units/mL 1 mL DOSETTE vial packaged in 25s (NDC 0641-0410-25) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 12 4 mL Multiple Dose vial packaged in 25s (NDC 0641-2470-45) Also available from Baxter: HEP-LOCK (Heparin Lock Flush Solution, USP) and HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP). Storage Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Baxter, Hep-Lock and Dosette are trademarks of Baxter International, Inc., or its subsidiaries. REFERENCES: 1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia – A Case Report – J Jpn Assn Torca Surg. 1992;40(3):110-111. 2. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of Internal Medicine. 2001;135:502-506. 3. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Internal Medicine, 2002;136:210-215. 4. Dieck, J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative for Heparin-Induced Thrombosis.”. Chest 98(1524-26). 5. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency Medicine, 2005;45(4):417-419 6. DIVGI A. (REPRINT), THUMMA S., HARI P., FRIEDMAN K., DELAYED ONSET HEPARIN- INDUCED THROMBOCYTOPENIA (HIT) PRESENTING AFTER UNDOCUMENTED DRUG EXPOSURE AS POST- ANGIOGRAPHY PULMONARY EMBOLISM.BLOOD.2003;102(11):127B. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-01119/3.0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 13 HEP-LOCK (Heparin Lock Flush Solution, USP) Rx only DESCRIPTION Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6- sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)>(1)>(4)>(3)>(5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. Structural formula of Heparin Sodium (representative sub-units): HEP-LOCK (Heparin Lock Flush Solution, USP) is a sterile solution for intravenous flush only. It is not to be used for anticoagulant therapy. Each mL contains heparin sodium 10 or 100 USP units, derived from porcine intestines and standardized for use as an anticoagulant, sodium chloride 9 mg and benzyl alcohol 0.01 mL in Water for Injection. pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid used, if needed, for pH adjustment. The potency is determined by biological assay using a USP reference standard based on units of heparin activity per milligram. CLINICAL PHARMACOLOGY Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 14 preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin. Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear, which suggests the absence of zero order processes. Liver and the reticulo-endothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t½ = 10 min), and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin. Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. INDICATIONS AND USAGE Heparin Lock Flush Solution, USP is intended to maintain patency of an indwelling venipuncture device designed for intermittent injection or infusion therapy or blood sampling. Heparin Lock Flush Solution may be used following initial placement of the device in the vein, after each injection of a medication or after withdrawal of blood for laboratory tests. (See DOSAGE AND ADMINISTRATION, Maintenance Of Patency Of Intravenous Devices for directions for use.) HEP-LOCK is not to be used for anticoagulant therapy. CONTRAINDICATIONS Heparin sodium should NOT be used in patients with the following conditions: severe thrombocytopenia; an uncontrollable active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation. WARNINGS Heparin is not intended for intramuscular use. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 15 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life- threatening situations. (See ADVERSE REACTIONS, Hypersensitivity.) Hemorrhage Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event. Heparin sodium should be used with extreme caution in infants and in patients with disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are: Cardiovascular Subacute bacterial endocarditis, severe hypertension. Surgical During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye. Hematologic Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Gastrointestinal Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other Menstruation, liver disease with impaired hemostasis. Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30%. Platelet counts should be obtained at baseline and periodically during heparin This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 16 administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued and, if necessary, an alternative anticoagulants administered. Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as Heparin-induced Thrombocytopenia and Thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation. Delayed Onset of HIT and HITT Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT. Use In Neonates This product contains the preservative benzyl alcohol and is not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Preservative-Free Heparin Lock Flush Solution, USP should be used for maintaining the patency of intravenous injection devices in neonates. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 17 PRECAUTIONS General In infants, the cumulative amounts of heparin and benzyl alcohol received from the frequent administration of Heparin Lock Flush Solution during a 24-hour period must be considered. Where preservative-free heparin lock flush solution is indicated, HEP-LOCK U/P is available. Precautions must be exercised when drugs that are incompatible with heparin are administered through an indwelling intravenous catheter containing Heparin Lock Flush Solution. (See DOSAGE AND ADMINISTRATION, Maintenance Of Patency Of Intravenous Devices.) Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) See WARNINGS. Increased Risk To Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. Laboratory Tests Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin use (see DOSAGE AND ADMINISTRATION). Drug Interactions Platelet Inhibitors Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. Other Interactions Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 18 Carcinogenesis, Mutagenesis, Impairment Of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of heparin sodium. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility. Pregnancy Teratogenic Effects—Pregnancy Category C Animal reproduction studies have not been conducted with heparin sodium. It is also not known whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Heparin sodium should be given to a pregnant woman only if clearly needed. Nonteratogenic Effects Heparin does not cross the placental barrier. Nursing Mothers Heparin is not excreted in human milk. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Not for use in neonates (see WARNINGS). Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see CLINICAL PHARMACOLOGY and PRECAUTIONS, General). ADVERSE REACTIONS Hemorrhage Hemorrhage is the chief complication that may result from heparin use (see WARNINGS, Hemorrhage). An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug (see OVERDOSAGE). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 19 Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT See WARNINGS. Local Irritation Local irritation and erythema have been reported with the use of Heparin Lock Flush Solution. Hypersensitivity Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur. Thrombocytopenia has been reported to occur in patients receiving heparin, with a reported incidence of 0 to 30%. While often mild and of no obvious clinical significance, such thrombocytopenia can be accompanied by severe thromboembolic complications such as skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death. (See WARNINGS and PRECAUTIONS.) Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated complications remains to be determined. OVERDOSAGE Symptoms Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. Treatment—Neutralization Of Heparin Effect When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 20 Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP products. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Slight discoloration does not alter potency. Heparin Lock Flush Solution is not recommended for use in neonates (see WARNINGS, Use In Neonates). Maintenance Of Patency Of Intravenous Devices To prevent clot formation in a heparin lock set or central venous catheter following its proper insertion, Heparin Lock Flush Solution, USP is injected via the injection hub in a quantity sufficient to fill the entire device. This solution should be replaced each time the device is used. Aspirate before administering any solution via the device in order to confirm patency and location of needle or catheter tip. If the drug to be administered is incompatible with heparin, the entire device should be flushed with normal saline before and after the medication is administered; following the second saline flush, Heparin Lock Flush Solution, USP may be reinstilled into the device. The device manufacturer's instructions should be consulted for specifics concerning its use. Usually this dilute heparin solution will maintain anticoagulation within the device for up to 4 hours. NOTE: Since repeated injections of small doses of heparin can alter tests for activated partial thromboplastin time (APTT), a baseline value for APTT should be obtained prior to insertion of an intravenous device. Withdrawal Of Blood Samples Heparin Lock Flush Solution, USP may also be used after each withdrawal of blood for laboratory tests. When heparin would interfere with or alter the results of blood tests, the heparin solution should be cleared from the device by aspirating and discarding it before withdrawing the blood sample. HOW SUPPLIED HEP-LOCK (Heparin Lock Flush Solution, USP) 10 USP units/mL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 21 1 mL DOSETTE vials packaged in 25s (NDC 0641-0392-25) 2 mL DOSETTE vials packaged in 25s (NDC 0641-0393-25) 10 mL Multiple Dose vials packaged in 25s (NDC 0641-2438-45) 30 mL Multiple Dose vials packaged in 25s (NDC 0641-2442-45) 100 USP units/mL 1 mL DOSETTE vials packaged in 25s (NDC 0641-0389-25) 2 mL DOSETTE vials packaged in 25s (NDC 0641-0387-25) 10 mL Multiple Dose vials packaged in 25s (NDC 0641-2436-45) 30 mL Multiple Dose vials packaged in 25s (NDC 0641-2443-45) Storage Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. REFERENCES 1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia – A Case Report – J Jpn Assn Torca Surg.1992;40(3):110-111. 2. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of Internal Medicine. 2001;135:502-506. 3. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Internal Medicine, 2002;136:210-215. 4. Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative for Heparin- Induced Thrombosis.” Chest 98(1524-26). 5. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency Medicine, 2005;45(4):417-419. 6. Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post-Angiography Pulmonary Embolism. Blood. 2003;102(11):127b. Hep-Lock, Baxter and Dosette are registered trademarks of Baxter International, Inc., or its subsidiaries. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 22 For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-00103/3.0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 23 HEP-LOCK U/P Preservative-Free (Heparin Lock Flush Solution, USP) Rx only DESCRIPTION Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6- sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)>(1)>(4)>(3)>(5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. Structural formula of Heparin Sodium (representative sub-units): HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP) is a sterile solution for intravenous flush only. It is not to be used for anticoagulant therapy. HEP-LOCK U/P is specially formulated for use in situations where the use of preservatives is not advisable. Each mL contains heparin sodium 10 or 100 USP units, derived from porcine intestines and standardized for use as an anticoagulant, sodium chloride 8 mg, monobasic sodium phosphate monohydrate 2.3 mg, and dibasic sodium phosphate anhydrous 0.5 mg in Water for Injection. pH 5.0-7.5. The potency is determined by biological assay using a USP reference standard based on units of heparin activity per milligram. CLINICAL PHARMACOLOGY Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 24 activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin. Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear, which suggests the absence of zero order processes. Liver and the reticulo-endothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t1/2 = 10 min), and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin. Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. INDICATIONS AND USAGE HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP) is intended to maintain patency of an indwelling venipuncture device designed for intermittent injection or infusion therapy or blood sampling. Heparin Lock Flush Solution may be used following initial placement of the device in the vein, after each injection of a medication or after withdrawal of blood for laboratory tests. (See DOSAGE AND ADMINISTRATION, Maintenance of Patency of Intravenous Devices for directions for use.) HEP-LOCK U/P is not to be used for anticoagulant therapy. CONTRAINDICATIONS Heparin sodium should NOT be used in patients with the following conditions: severe thrombocytopenia; an uncontrollable active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation. WARNINGS Heparin is not intended for intramuscular use. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 25 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life- threatening situations. (See ADVERSE REACTIONS, Hypersensitivity.) Hemorrhage Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event. Heparin sodium should be used with extreme caution in infants and in patients with disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are: Cardiovascular Subacute bacterial endocarditis, severe hypertension. Surgical During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye. Hematologic Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Gastrointestinal Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other Menstruation, liver disease with impaired hemostasis. Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30%. Platelet counts should be obtained at baseline and periodically during heparin This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 26 administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued and, if necessary, an alternative anticoagulant administered. Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as Heparin-induced Thrombocytopenia and Thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation. Delayed Onset of HIT and HITT Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT. Use in Neonates and Infants The 100 unit/mL concentration should not be used in neonates or in infants who weigh less than 10 kg because of the risk of systemic anticoagulation. Caution is necessary when using the 10 unit/mL concentration in premature infants who weigh less than 1 kg who are receiving frequent flushes since a therapeutic heparin dose may be given to the infant in a 24-hour period. PRECAUTIONS General Precautions must be exercised when drugs that are incompatible with heparin are administered through an indwelling intravenous catheter containing Preservative-Free Heparin Lock Flush Solution. (See DOSAGE AND ADMINISTRATION, Maintenance of Patency of Intravenous Devices.) The concentration of phosphorus in the heparin solution is 0.63 mg/mL. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 27 Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) See WARNINGS. Increased Risk to Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. Laboratory Tests Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin use (see DOSAGE AND ADMINISTRATION). Drug Interactions Platelet Inhibitors Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. Other Interactions Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of heparin sodium. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility. Pregnancy Teratogenic Effects—Pregnancy Category C Animal reproduction studies have not been conducted with heparin sodium. It is also not known whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Heparin sodium should be given to a pregnant woman only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 28 Nonteratogenic Effects Heparin does not cross the placental barrier. Nursing Mothers Heparin is not excreted in human milk. Pediatric Use Safety and effectiveness in pediatric patients have not been established (see WARNINGS, Use in Neonates and Infants). Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see CLINICAL PHARMACOLOGY and PRECAUTIONS, General). ADVERSE REACTIONS Hemorrhage Hemorrhage is the chief complication that may result from heparin use (see WARNINGS, Hemorrhage). An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug (see OVERDOSAGE). Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT See WARNINGS. Local Irritation Local irritation and erythema have been reported with the use of Heparin Lock Flush Solution. Hypersensitivity Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 29 Thrombocytopenia has been reported to occur in patients receiving heparin, with a reported incidence of 0 to 30%. While often mild and of no obvious clinical significance, such thrombocytopenia can be accompanied by severe thromboembolic complications such as skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death. (See WARNINGS and PRECAUTIONS.) Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated complications remains to be determined. OVERDOSAGE Symptoms Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. Treatment—Neutralization of Heparin Effect When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP products. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Slight discoloration does not alter potency. Preservative-Free Heparin Lock Flush Solution in the 100 unit/mL concentration is not recommended for use in neonates and infants (see WARNINGS, Use In Neonates and Infants). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 30 Maintenance of Patency of Intravenous Devices To prevent clot formation in a heparin lock set or central venous catheter following its proper insertion, Preservative-Free Heparin Lock Flush Solution, USP is injected via the injection hub in a quantity sufficient to fill the entire device. This solution should be replaced each time the device is used. Aspirate before administering any solution via the device in order to confirm patency and location of needle or catheter tip. If the drug to be administered is incompatible with heparin, the entire device should be flushed with normal saline before and after the medication is administered; following the second saline flush, Preservative-Free Heparin Lock Flush Solution, USP may be reinstilled into the device. The device manufacturer's instructions should be consulted for specifics concerning its use. Usually this dilute heparin solution will maintain anticoagulation within the device for up to 4 hours. NOTE: Since repeated injections of small doses of heparin can alter tests for activated partial thromboplastin time (APTT), a baseline value for APTT should be obtained prior to insertion of an intravenous device. Withdrawal of Blood Samples Preservative-Free Heparin Lock Flush Solution, USP may also be used after each withdrawal of blood for laboratory tests. When heparin would interfere with or alter the results of blood tests, the heparin solution should be cleared from the device by aspirating and discarding it before withdrawing the blood sample. HOW SUPPLIED HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP) 10 USP units/mL 1 mL DOSETTE vials packaged in 25s (NDC 0641-0272-25) 100 USP units/mL 1 mL DOSETTE vials packaged in 25s (NDC 0641-0273-25) Storage Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. REFERENCES 7. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia – A Case Report – J Jpn Assn Torca Surg.1992;40(3):110-111. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-037/S-158 Page 31 8. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of Internal Medicine. 2001;135:502-506. 9. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Internal Medicine, 2002;136:210-215. 10. Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative for Heparin- Induced Thrombosis.” Chest 98(1524-26). 11. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency Medicine, 2005;45(4):417-419. 12. Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post-Angiography Pulmonary Embolism. Blood. 2003;102(11):127b. ESI logo, Hep-Lock and Dosette are registered trademarks of Baxter International, Inc., or its subsidiaries. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-00090/5.0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:07.196104	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017037s158lbl.pdf', 'application_number': 17037, 'submission_type': 'SUPPL ', 'submission_number': 158}
10,955	CEBERT PHARMACEUTICALS, INC. DISKETS® Dispersible Tablets CII (Methadone Hydrochloride Tablets, USP), 40 mg Rx only FOR ORAL USE ONLY (Following Dispersion in a Liquid) Deaths have been reported during initiation of methadone treatment for opioid dependence. In some cases, drug interactions with other drugs, both licit and illicit, have been suspected. However, in other cases, deaths appear to have occurred due to the respiratory or cardiac effects of methadone and too-rapid titration without appreciation for the accumulation of methadone over time. It is critical to understand the pharmacokinetics of methadone and to exercise vigilance during treatment initiation and dose titration (see DOSAGE AND ADMINISTRATION). Patients must also be strongly cautioned against self-medicating with CNS depressants during initiation of methadone treatment. Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, particularly in the early dosing period. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. _______________________________________________________________________ Conditions for Distribution and Use of Methadone Products for the Treatment of Opioid Addiction Code of Federal Regulations, Title 42, Sec 8 Methadone products when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by opioid treatment programs (and agencies, practitioners or institutions by formal agreement with the program sponsor) certified by the Substance Abuse and Mental Health Services Administration and approved by the designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards (42 CFR 8.12). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment. Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval, and injunction precluding operation of the program. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Regulatory Exceptions to the General Requirement for Certification to Provide Opioid Agonist Treatment: 1. During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21 CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis. 2. During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21 CFR 1306.07(b)). DESCRIPTION DISKETS® Dispersible Tablets (Methadone Hydrochloride Tablets, USP), is for oral administration following dispersion in a liquid. Each tablet contains 40 mg of methadone hydrochloride. Methadone hydrochloride is chemically described as (3-heptanone, 6-(dimethylamino)-4, 4- diphenyl-, hydrochloride). Methadone hydrochloride is a white, essentially odorless, bitter- tasting crystalline powder. It is very soluble in water, soluble in isopropranolol and in chloroform, and practically insoluble in ether and in glycerine. It is present in DISKETS as the racemic mixture. Methadone hydrochloride has a melting point of 235ºC, a pKa of 8.25 in water at 20°C, a solution (1 in 100) pH between 4.5 and 6.5, a partition coefficient of 117 at pH 7.4 in octanol/water and a molecular weight of 345.91. Its molecular formula is C21H27NO•HCl and its structural formula is: The Diskets preparation of methadone hydrochloride contains insoluble excipients and must not be injected. Other ingredients of Diskets include: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, orange lake color, orange-pineapple flavor, potassium phosphate monobasic, pregelatinized starch, and stearic acid. CLINICAL PHARMACOLOGY Mechanism of Action Methadone hydrochloride is a mu-agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle. The principal therapeutic uses for methadone are analgesia and detoxification or maintenance in opioid addiction. The methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. CCH2CH3 CH2CHN CH3 CH3 CH3 O . HCl C This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals. Pharmacokinetics Absorption Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 to 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated. Distribution Methadone is a lipophilic drug and the steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 90%). Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma. Metabolism Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, CYP2C19, and to a lesser extent CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the urine. Excretion The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Published reports indicate that after multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 to 126 L/h, and the terminal half-life (T1/2) was highly variable and ranged between 8 to 59 hours in different studies. Since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations. Pharmacokinetics in Special Populations Pregnancy The disposition of oral methadone has been studied in approximately 30 pregnant patients in the 2nd and 3rd trimesters. Elimination of methadone was significantly changed in pregnancy. Total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women. The terminal half-life of methadone is decreased during 2nd and 3rd trimesters. The decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may need to be increased or the dosing interval decreased in pregnant patients receiving methadone. (See PRECAUTIONS: Pregnancy, Labor and Delivery, and DOSAGE AND ADMINISTRATION.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal Impairment Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree. Methadone is a basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in plasma. Urine acidification has been shown to increase renal elimination of methadone. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for increasing the elimination of methadone or its metabolites. Hepatic Impairment Methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized by hepatic pathways, therefore patients with liver impairment may be at risk of accumulating methadone after multiple dosing. Gender The pharmacokinetics of methadone have not been evaluated for gender specificity. Race The pharmacokinetics of methadone have not been evaluated for race specificity. Geriatric The pharmacokinetics of methadone have not been evaluated in the geriatric population. Pediatric The pharmacokinetics of methadone have not been evaluated in the pediatric population. Drug Interactions (see PRECAUTIONS: Drug Interactions) Methadone undergoes hepatic N-demethylation by cytochrome P-450 isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with inducers of these enzymes may result in more rapid methadone metabolism, and potentially, decreased effects of methadone. Conversely, administration with CYP inhibitors may reduce metabolism and potentiate methadone’s effects. Pharmacokinetics of methadone may be unpredictable when coadministered with drugs that are known to both induce and inhibit CYP enzymes. Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to their CYP induction activity. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy before making a dosage adjustment. INDICATIONS AND USAGE 1. For detoxification treatment of opioid addiction (heroin or other morphine-like drugs). 2. For maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOTE Outpatient maintenance and outpatient detoxification treatment may be provided only by Opioid Treatment Programs (OTPs) certified by the Federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA). This does not preclude the maintenance treatment of a patient with concurrent opioid addiction who is hospitalized for conditions other than opioid addiction and who requires temporary maintenance during the critical period of his/her stay, or of a patient whose enrollment has been verified in a program which has been certified for maintenance treatment with methadone. CONTRAINDICATIONS DISKETS are contraindicated in patients with a known hypersensitivity to methadone hydrochloride or any other ingredient in DISKETS. Methadone is contraindicated in any situation where opioids are contraindicated such as: patients with respiratory depression (in the absence of resuscitative equipment or in unmonitored settings), and in patients with acute bronchial asthma or hypercarbia. Methadone is contraindicated in any patient who has or is suspected of having a paralytic ileus. WARNINGS Respiratory Depression Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and central nervous system (CNS) depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Methadone should be used at the lowest effective dose and only under careful medical supervision. Cardiac Conduction Effects This information is intended to alert the prescriber to comprehensively evaluate the risks and benefits of methadone treatment. The intent is not to deter the appropriate use of methadone in patients with a history of cardiac disease. Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Although most cases involve patients being treated for pain with large, multiple daily doses of methadone, cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most of the cases seen at typical maintenance doses, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction abnormalities, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone. Patients developing QT prolongation while on methadone treatment should be evaluated for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities and drugs which might act as inhibitors of methadone metabolism. The potential risks of methadone, including the risk of life-threatening arrhythmias, should be weighed against the risks of discontinuing methadone treatment. In the patient being treated for opiate dependence with methadone maintenance therapy, these risks include a very high likelihood of relapse to illicit drug use following methadone discontinuation. The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied. The potential risks of methadone should be weighed against the substantial morbidity and mortality associated with untreated opioid addiction. In using methadone an individualized benefit to risk assessment should be carried out and should include evaluation of patient presentation and complete medical history. For patients judged to be at risk, careful monitoring of cardiovascular status, including evaluation of QT prolongation and dysrhythmias should be performed. Incomplete Cross-tolerance between Methadone and other Opioids Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross- tolerance is of particular concern for patients tolerant to other mu-opioid agonists who are being converted to methadone, thus making determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Misuse, Abuse, and Diversion of Opioids Methadone is a mu-agonist opioid with an abuse liability similar to that of morphine and other opioid agonists and is a Schedule II controlled substance. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Diskets in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion. Abuse of methadone poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone with alcohol and other substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Interactions with other CNS Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with methadone may experience respiratory depression, hypotension, profound sedation, or coma (see PRECAUTIONS). Interactions with Alcohol and Drugs of Abuse Methadone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Deaths associated with illicit use of methadone frequently have involved concomitant benzodiazepine abuse. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal-fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential. Acute Abdominal Conditions The administration of opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Hypotensive Effect The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion). PRECAUTIONS DISKETS should be used with caution in elderly and debilitated patients; patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease; and in patients with comorbid conditions or concomitant medications which may predispose to dysrhythmia or reduced ventilatory drive. Drug Interactions In vitro results suggest that methadone undergoes hepatic N-demethylation by cytochrome P450 enzymes, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CYP2D6. Coadministration of methadone with inducers of these enzymes may result in a more rapid metabolism and potential for decreased effects of methadone, whereas administration with CYP inhibitors may reduce metabolism and potentiate methadone’s effects. Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit CYPs, they are shown to reduce the plasma levels of methadone, possibly due to their CYP induction activity. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy. Opioid Antagonists, Mixed Agonist/Antagonists, and Partial Agonists As with other mu-agonists, patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists. Examples of such agents are naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine. Anti-retroviral Agents Abacavir, amprenavir, efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination – Coadministration of these anti-retroviral agents resulted in increased clearance or decreased plasma levels of methadone. Methadone-maintained patients beginning treatment with these antiretroviral drugs should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly. Didanosine and Stavudine – Experimental evidence demonstrated that methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered. Zidovudine – Experimental evidence demonstrated that methadone increased the area under the concentration-time curve (AUC) of zidovudine which could result in toxic effects. Cytochrome P450 Inducers Methadone-maintained patients beginning treatment with CYP3A4 inducers should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly. The following drug interactions were reported following coadministration of methadone with inducers of cytochrome P450 enzymes: Rifampin – In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms. Phenytoin – In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i.d. initially for 1 day followed by 300 mg QD for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda St. John’s Wort, Phenobarbital, Carbamazepine Administration of methadone along with other CYP3A4 inducers may result in withdrawal symptoms. Cytochrome P450 Inhibitors Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. The expected clinical results would be increased or prolonged opioid effects. Thus, methadone-treated patients coadministered strong inhibitors of CYP3A4, such as azole antifungal agents (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin), with methadone should be carefully monitored and dosage adjustment should be undertaken if warranted. Some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine) may increase methadone plasma levels upon coadministration with methadone and result in increased opiate effects and/or toxicity. Voriconazole – Repeat dose administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 4 days) increased the Cmax and AUC of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg QD). The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed. Others Monoamine Oxidase (MAO) Inhibitors – Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone. However, if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small, incremental doses of methadone are administered over the course of several hours while the patient's condition and vital signs are under careful observation. Desipramine – Blood levels of desipramine have increased with concurrent methadone administration. Potentially Arrhythmogenic Agents Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Caution should also be exercised when treating methadone patients concomitantly with drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval. These drugs include diuretics, laxatives, and, in rare cases, mineralocorticoid hormones. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Interactions with Alcohol and Drugs of Abuse Methadone may be expected to have additive effects when used in conjunction with alcohol, other opioids or CNS depressants, or with illicit drugs that cause central nervous system depression. Deaths have been reported when methadone has been abused in conjunction with benzodiazepines. Anxiety – Since methadone as used by tolerant patients at a constant maintenance dosage does not act as a tranquilizer, patients who are maintained on this drug will react to life problems and stresses with the same symptoms of anxiety as do other individuals. The physician should not confuse such symptoms with those of narcotic abstinence and should not attempt to treat anxiety by increasing the dose of methadone. The action of methadone in maintenance treatment is limited to the control of narcotic withdrawal symptoms and is ineffective for relief of general anxiety. Acute Pain – Maintenance patients on a stable dose of methadone who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. Due to the opioid tolerance induced by methadone, when opioids are required for management of acute pain in methadone patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients. Physical Dependence Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence is expected during opioid agonist therapy of opioid addiction. If a physically dependent patient abruptly discontinues use of methadone, or the dose of methadone does not adequately “cover” the patient, an opioid abstinence or withdrawal syndrome may develop and is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms may also develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids may also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see PRECAUTIONS: Pregnancy, Labor and Delivery). In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: For Medically Supervised Withdrawal After a Period of Maintenance Treatment). Special-Risk Patients – Methadone should be given with caution, and the initial dose reduced, in certain patients such as the elderly and debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy, or urethral stricture. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The usual precautions should be observed and the possibility of respiratory depression requires added vigilance. Information for Patients • Patients should be cautioned that methadone, like all opioids, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving or operating machinery. • Patients should be cautioned that methadone, like other opioids, may produce orthostatic hypotension in ambulatory patients. • Patients should be cautioned that alcohol and other CNS depressants may produce an additive CNS depression when taken with this product and should be avoided. • Patients should be instructed to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, or syncope) when taking methadone. • Patients initiating treatment with methadone should be reassured that the dose of methadone will “hold” for longer periods of time as treatment progresses. • Patients should be instructed to keep methadone in a secure place out of the reach of children and other household members. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. • Patients should be advised not to change the dose of methadone without consulting their physician. • Women of childbearing potential who become or are planning to become pregnant should be advised to consult their physician regarding the effects of methadone use during pregnancy on themselves and their unborn child. • If a physically dependent patient abruptly discontinues use of methadone, an opioid abstinence or withdrawal syndrome may develop. If cessation of therapy is indicated, it may be appropriate to taper the methadone dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication. • Patients seeking to discontinue treatment with methadone for opioid dependence should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment. • Patients should be advised that methadone is a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • DISKETS are for oral administration only and must be initially dispersed in liquid before use. After dispersion in liquid, the preparation must not be injected. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis – The results of carcinogenicity assessment in B6C2F1 mice and Fischer 344 rats following dietary administration of two doses of methadone HCl have been published. Mice consumed 15 mg/kg/day or 60 mg/kg/day methadone for two years. These doses were approximately 0.6 and 2.5 times a human daily oral dose of 120 mg/day on a body surface area basis (mg/m2). There was a significant increase in pituitary adenomas in female mice treated with 15 mg/kg/day but not with 60 mg/kg/day. Under the conditions of the assay, there was no clear evidence for a treatment-related increase in the incidence of neoplasms in male rats. Due to decreased food consumption in males at the high dose, male rats consumed 16 mg/kg/day and 28 mg/kg/day of methadone for two years. These doses were approximately 1.3 and 2.3 times a human daily oral dose of 120 mg/day, based on body surface area comparison. In contrast, female rats consumed 46 mg/kg/day or 88 mg/kg/day for two years. These doses were approximately 3.7 and 7.1 times a human daily oral dose of 120 mg/day, based on body surface area comparison. Under the conditions of the assay, there was no clear evidence for a treatment- related increase in the incidence of neoplasms in either male or female rats. Mutagenesis – There are several published reports on the potential genetic toxicity of methadone. Methadone tested negative in tests for chromosome breakage and disjunction and sex-linked recessive lethal gene mutations in germ cells of Drosophila using feeding and injection procedures. In contrast, methadone tested positive in the in vivo mouse dominant lethal assay and the in vivo mammalian spermatogonial chromosome aberration test. Additionally, methadone tested positive in the E.coli DNA repair system and Neurospora crassa and mouse lymphoma forward mutation assays. Fertility – Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. Published animal studies provide additional data indicating that methadone treatment of males can alter reproductive function. Methadone produces a significant regression of sex accessory organs and testes of male mice and rats. Additional data have been published indicating that methadone treatment of male rats (once a day for three consecutive days) increased embryolethality and neonatal mortality. Examination of uterine contents of methadone-naive female mice bred to methadone-treated mice indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states. Pregnancy Teratogenic Effects – Pregnancy Category C. There are no controlled studies of methadone use in pregnant women that can be used to establish safety. However, an expert review of published data on experiences with methadone use during pregnancy by the Teratogen Information System (TERIS) concluded that maternal use of methadone during pregnancy as part of a supervised, therapeutic regimen is unlikely to pose a substantial teratogenic risk (quantity and quality of data assessed as “limited to fair”). However, the data are insufficient to state that there is no risk (TERIS, last reviewed October, 2002). Pregnant women involved in methadone maintenance This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda programs have been reported to have significantly improved prenatal care leading to significantly reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Several factors complicate the interpretation of investigations of the children of women who take methadone during pregnancy. These include the maternal use of illicit drugs, other maternal factors such as nutrition, infection, and psychosocial circumstances, limited information regarding dose and duration of methadone use during pregnancy, and the fact that most maternal exposure appears to occur after the first trimester of pregnancy. Reported studies have generally compared the benefit of methadone to the risk of untreated addiction to illicit drugs. Methadone has been detected in amniotic fluid and cord plasma at concentrations proportional to maternal plasma and in newborn urine at lower concentrations than corresponding maternal urine. A retrospective series of 101 pregnant, opiate-dependent women who underwent inpatient opiate detoxification with methadone did not demonstrate any increased risk of miscarriage in the second trimester or premature delivery in the third trimester. Several studies have suggested that infants born to narcotic-addicted women treated with methadone during all or part of pregnancy have been found to have decreased fetal growth with reduced birth weight, length, and/or head circumference compared to controls. This growth deficit does not appear to persist into later childhood. However, children born to women treated with methadone during pregnancy have been shown to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests. Additional information on the potential risks of methadone may be derived from animal data. Methadone does not appear to be teratogenic in the rat or rabbit models. However, following large doses, methadone produced teratogenic effects in the guinea pig, hamster and mouse. One published study in pregnant hamsters indicated that a single subcutaneous dose of methadone ranging from 31 to 185 mg/kg (the 31 mg/kg dose is approximately 2 times a human daily oral dose of 120 mg/day on a mg/m2 basis) on day 8 of gestation resulted in a decrease in the number of fetuses per litter and an increase in the percentage of fetuses exhibiting congenital malformations described as exencephaly, cranioschisis, and “various other lesions.” The majority of the doses tested also resulted in maternal death. In another study, a single subcutaneous dose of 22 to 24 mg/kg methadone (estimated exposure was approximately equivalent to a human daily oral dose of 120 mg/day on a mg/m2 basis) administered on day 9 of gestation in mice also produced exencephaly in 11% of the embryos. However, no effects were reported in rats and rabbits at oral doses up to 40 mg/kg (estimated exposure was approximately 3 and 6 times, respectively, a human daily oral dose of 120 mg/day on a mg/m2 basis) administered during days 6 to 15 and 6 to 18, respectively. Nonteratogenetic Effects – Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. Onset of withdrawal symptoms in infants is usually in the first days after birth. Withdrawal signs in the newborn include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the maternal dose or the duration of maternal exposure. The duration of the withdrawal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda signs may vary from a few days to weeks or even months. There is no consensus on the appropriate management of infant withdrawal. There are conflicting reports on whether SIDS occurs with an increased incidence in infants born to women treated with methadone during pregnancy. Abnormal fetal nonstress tests (NSTs) have been reported to occur more frequently when the test is performed 1 to 2 hours after a maintenance dose of methadone in late pregnancy compared to controls. Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone prior to mating. In these studies, the female rodents were not treated with methadone, indicating paternally-mediated developmental toxicity. Specifically, methadone administered to the male rat prior to mating with methadone-naïve females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. Furthermore, behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals, suggesting that paternal methadone exposure can produce physiological and behavioral changes in progeny in this model. Other animal studies have reported that perinatal exposure to opioids including methadone alters neuronal development and behavior in the offspring. Perinatal methadone exposure in rats has been linked to alterations in learning ability, motor activity, thermal regulation, nociceptive responses and sensitivity to drugs. Additional animal data demonstrates evidence for neurochemical changes in the brains of methadone-treated offspring, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems. Additional studies demonstrated that methadone treatment of male rats for 21 to 32 days prior to mating with methadone-naïve females did not produce any adverse effects, suggesting that prolonged methadone treatment of the male rat resulted in tolerance to the developmental toxicities noted in the progeny. Mechanistic studies in this rat model suggest that the developmental effects of “paternal” methadone on the progeny appear to be due to decreased testosterone production. These animal data mirror the reported clinical findings of decreased testosterone levels in human males on methadone maintenance therapy for opioid addiction and in males receiving chronic intraspinal opioids. Clinical Pharmacology for Pregnancy– Pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery. Dosage adjustment using higher doses or administering the daily dose in divided doses may be necessary in pregnant women treated with methadone. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Methadone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery As with all opioids, administration of this product to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. Methadone is not recommended for obstetric analgesia because its long duration of action This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda increases the probability of respiratory depression in the newborn. Narcotics with mixed agonist-antagonist properties should not be used for pain control during labor in patients chronically treated with methadone as they may precipitate acute withdrawal. Nursing Mothers Methadone is secreted into human milk. The safety of breastfeeding while taking oral methadone is controversial. At maternal oral doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk have been reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone. Women on high dose methadone maintenance, who are already breast feeding, should be counseled to wean breast-feeding gradually in order to prevent neonatal abstinence syndrome. Methadone-treated mothers considering nursing an opioid-naïve infant should be counseled regarding the presence of methadone in breast milk. Because of the potential for serious adverse reactions in nursing infants from methadone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother, and weighing the risk of methadone against the risk of maternal illicit drug use. Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Patients and caregivers should be instructed to keep methadone in a secure place out of the reach of children and to discard unused methadone in such a way that individuals other than the patient for whom it was originally prescribed will not come in contact with the drug. Geriatric Use Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Renal Impairment The use of methadone has not been extensively evaluated in patients with renal insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatic Impairment The use of methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized in the liver and patients with liver impairment may be at risk of accumulating methadone after multiple dosing. Gender The use of methadone has not been evaluated for gender specificity. ADVERSE REACTIONS Heroin Withdrawal During the induction phase of methadone maintenance treatment, patients are being withdrawn from heroin and may therefore show typical withdrawal symptoms, which should be differentiated from methadone-induced side effects. They may exhibit some or all of the following signs and symptoms associated with acute withdrawal from heroin or other opiates: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilliness alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss. Initial Administration The initial methadone dose should be carefully titrated to the individual. Too rapid titration for the patient’s sensitivity is more likely to produce adverse effects. The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, and death have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable. Other adverse reactions include the following: (listed alphabetically under each subsection) Body as a Whole – asthenia (weakness), edema, headache Cardiovascular (also see WARNINGS: Cardiac Conduction Effects) – arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsade de pointes, ventricular fibrillation, ventricular tachycardia Digestive – abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis Hematologic and Lymphatic – reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis Metabolic and Nutritional – hypokalemia, hypomagnesemia, weight gain Nervous – agitation, confusion, disorientation, dysphoria, euphoria, insomnia, seizures This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Respiratory – pulmonary edema, respiratory depression (see WARNINGS: Respiratory Depression) Skin and Appendages – pruritis, urticaria, other skin rashes, and rarely, hemorrhagic urticaria Special Senses – hallucinations, visual disturbances Urogenital – amenorrhea, antidiuretic effect, reduced libido and/or potency, urinary retention or hesitancy Maintenance on a Stabilized Dose – During prolonged administration of methadone, as in a methadone maintenance treatment program, there is usually a gradual, yet progressive, disappearance of side effects over a period of several weeks. However, constipation and sweating often persist. DRUG ABUSE AND DEPENDENCE DISKETS contains methadone, a potent Schedule II opioid agonist. Schedule II opioid substances, which also include hydromorphone, morphine, oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. Abuse of methadone poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone with alcohol and other substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Since methadone may be diverted for non-medical use, careful record keeping of ordering and dispensing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Methadone, when used for the treatment of opioid addiction in detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration (and agencies, practitioners or institutions by formal agreement with the program sponsor). Infants born to mothers physically dependent on opioids may also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (See PRECAUTIONS; Pregnancy, Labor and Delivery). OVERDOSAGE Signs and Symptoms Serious overdosage of methadone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, maximally constricted pupils, skeletal-muscle flaccidity, cold and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda clammy skin, and sometimes, bradycardia and hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. If a non-tolerant person, takes a large dose of methadone, effective opioid antagonists are available to counteract the potentially lethal respiratory depression. The physician must remember, however, that methadone is a long-acting depressant (36 to 48 hours), whereas opioid antagonists act for much shorter periods (one to three hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and may need to be treated repeatedly with the narcotic antagonist. If the diagnosis is correct and respiratory depression is due only to overdosage of methadone, the use of other respiratory stimulants is not indicated. Opioid antagonists should not be administered in the absence of clinically significant respiratory or cardiovascular depression. In an individual physically dependent on opioids, the administration of the usual dose of an opioid antagonist may precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. If antagonists must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist. Intravenously administered naloxone or nalmefene may be used to reverse signs of intoxication. Because of the relatively short half-life of naloxone as compared with methadone, repeated injections may be required until the status of the patient remains satisfactory. Naloxone may also be administered by continuous intravenous infusion. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. DOSAGE AND ADMINISTRATION Methadone differs from many other opioid agonists in several important ways. Methadone's pharmacokinetic properties, coupled with high interpatient variability in its absorption, metabolism, and relative analgesic potency, necessitate a cautious and highly individualized approach to prescribing. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration. While methadone’s duration of analgesic action (typically 4 to 8 hours) in the setting of single- dose studies approximates that of morphine, methadone’s plasma elimination half-life is substantially longer than that of morphine (typically 8 to 59 hours vs. 1 to 5 hours). Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. Also, with repeated dosing, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations. For these reasons, steady-state plasma concentrations, and full analgesic effects, are usually not attained until 3 to 5 days of dosing. Additionally, incomplete cross-tolerance between mu-opioid agonists makes determination of dosing during opioid conversion complex. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The complexities associated with methadone dosing can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high- dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. Detoxification and Maintenance Treatment of Opiate Dependence For detoxification and maintenance of opiate dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration. DISKETS are intended for dispersion in a liquid immediately prior to oral administration of the prescribed dose. The tablets should not be chewed or swallowed before dispersing in liquid. DISKETS are cross-scored, allowing for flexible dosage adjustment. Each tablet may be broken or cut in half to yield two 20-mg doses, or in quarters to yield four 10-mg doses. Prior to administration, the desired dose of DISKETS should be dispersed in approximately 120 mL (4 ounces) of water, orange juice, Tang®, citrus flavors of Kool-Aid® or other acidic fruit beverage prior to taking. Methadone hydrochloride is very soluble in water, but there are some insoluble excipients that will not entirely dissolve. If residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture administered to the patient. Induction/Initial Dosing The initial methadone dose should be administered, under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. Initially, a single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg. If same-day dosing adjustments are to be made, the patient should be asked to wait 2 to 4 hours for further evaluation, when peak levels have been reached. An additional 5 to 10 mg of methadone may be provided if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Dose adjustments should be made over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). Dose adjustment should be cautious; deaths have occurred in early treatment due to the cumulative effects of the first several days’ dosing. Because DISKETS can be administered only in 10 mg increments, DISKETS may not be the appropriate product for initial dosing in many patients. Patients should be reminded that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate. Initial doses should be lower for patients whose tolerance is expected to be low at treatment entry. Loss of tolerance should be considered in any patient who has not taken opioids for more than 5 days. Initial doses should not be determined by previous treatment episodes or dollars spent per day on illicit drug use. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For Short-term Detoxification For patients preferring a brief course of stabilization followed by a period of medically supervised withdrawal, it is generally recommended that the patient be titrated to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. Stabilization can be continued for 2 to 3 days, after which the dose of methadone should be gradually decreased. The rate at which methadone is decreased should be determined separately for each patient. The dose of methadone can be decreased on a daily basis or at 2-day intervals, but the amount of intake should remain sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20% of the total daily dose may be tolerated. In ambulatory patients, a somewhat slower schedule may be needed. Because DISKETS can be administered only in 10 mg increments, DISKETS may not be the appropriate product for gradual dose reduction in many patients. For Maintenance Treatment Patients in maintenance treatment should be titrated to a dose at which opioid symptoms are prevented for 24 hours, drug hunger or craving is reduced, the euphoric effects of self- administered opioids are blocked or attenuated, and the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day. For Medically Supervised Withdrawal After a Period of Maintenance Treatment There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14-day intervals should elapse between dose reductions. Because DISKETS can be administered only in 10 mg increments, it may not be the appropriate product for gradual dose reduction in many patients. Patients should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment. HOW SUPPLIED DISKETS® Dispersible Tablets (Methadone Hydrochloride Tablets USP), 40 mg 40 mg peach cross-scored tablets (Identified 54 883). NDC 64019-538-25: Bottles of 100 tablets. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. DISKETS, if dispensed, must be packaged in child-resistant containers and kept out of reach of children to prevent accidental ingestion. Mfd. by: Roxane Laboratories, Inc. Columbus, Ohio 43216 Dist. by: Cebert Pharmaceuticals, Inc. Birmingham, Alabama 35242 10000879/03 Revised October 2006 © RLI, 2006 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CEBERT LOGO HERE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:07.486701	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017058s017lbl.pdf', 'application_number': 17058, 'submission_type': 'SUPPL ', 'submission_number': 17}
10,956	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DISKETS safely and effectively. See full prescribing information for DISKETS. DISKETS Dispersible Tablets (methadone hydrochloride tablets for oral suspension) CII Initial U.S. Approval: 1973 WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT PROLONGATION, ACCIDENTAL EXPOSURE, ABUSE POTENTIAL and TREATMENT FOR OPIOID ADDICTION See full prescribing information for complete boxed warning • Fatal respiratory depression may occur, with highest risk at initiation and with dose increases. Instruct patients on proper administration of DISKETS Dispersible Tablets to reduce the risk. (5.1) • QT Interval prolongation and serious arrhythmia (torsades de pointes) have occurred with treatment with methadone. (5.2) • Accidental ingestion of DISKETS Dispersible Tablets can result in fatal overdose of methadone, especially in children. (5.3) • DISKETS Dispersible Tablets contain methadone, a Schedule II controlled substance and can be abused and criminally diverted. (5.4, 9) • Methadone products, when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by certified opioid treatment programs as stipulated in 42 CFR 8.12. (1) ----------------------------INDICATIONS AND USAGE------------------------- DISKETS Dispersible Tablets are an opioid agonist indicated for the: • Detoxification treatment of opioid addiction (heroin or other morphine-like drugs) (1) • Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. (1) -------------------------DOSAGE AND ADMINISTRATION--------------------- • Initiation of detoxification and maintenance treatment: A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. (2.1) • Do not abruptly discontinue DISKETS Dispersible Tablets in a physically dependent patient (2.3, 5.12) • Maintenance treatment: Clinical stability is most commonly achieved at doses between 80 to 120 mg/day. (2.2) -------------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets intended for dispersion in a liquid immediately prior to oral administration: 40 mg. (3) ---------------------------------CONTRAINDICATIONS--------------------------- • Significant respiratory depression (4) • Acute or severe bronchial asthma (4) • Known or suspected paralytic ileus (4) • Known hypersensitivity to methadone (4) --------------------------WARNINGS AND PRECAUTIONS--------------------- • Elderly, cachectic, and debilitated patients, and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. (5.5, 5.6) • Interactions with CNS depressants: Consider dose reduction of one or both drugs because of additive effects. (5.7, 7.2) • Hypotensive effect: Monitor during dose initiation and titration. (5.8) • Patients with head injury and increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of methadone in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention (5.9) --------------------------------ADVERSE REACTIONS--------------------------- Most common adverse reactions are: lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. (6) To report SUSPECTED ADVERSE REACTIONS, contact Roxane Laboratories, Inc. at 800-962-8364 or FDA at 1-800- FDA-1088 or www.fda.gov/medwatch --------------------------------DRUG INTERACTIONS-------------------------- • CYP3A4 Inducers: Increased risk of more rapid metabolism and decreased effects of methadone. (7.1) • CYP3A4 Inhibitors: Increased risk of reduced metabolism and methadone toxicity. (7.1) • Anti-retroviral Agents: May result in increased clearance and decreased plasma levels of methadone or in certain cases, increased plasma levels and risk of toxicity. (7.1) • Potentially Arrhythmogenic Agents: Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. (7.3) • Opioid antagonists, partial agonists, mixed agonists/antagonist opioid analgesics: Avoid concomitant use with DISKETS Dispersible Tablets because it may precipitate withdrawal symptoms. (5.12, 7.4) -------------------------USE IN SPECIFIC POPULATIONS-------------------- • Pregnancy: Based on animal data, may cause fetal harm. (8.1) • Nursing mothers: Methadone has been detected in human milk. Closely monitor infants of nursing women receiving DISKETS Dispersible Tablets. (8.3) See 17 for PATIENT COUNSELING INFORMATION Revised: 9 /2013 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT PROLONGATION, ACCIDENTAL EXPOSURE, ABUSE POTENTIAL and TREATMENT FOR OPIOID ADDICTION 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction 2.2 Titration and Maintenance Treatment of Opioid Dependence 2.3 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction 2.4 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction 2.5 Considerations for Management of Acute Pain During Methadone Maintenance Treatment 2.6 Dosage Adjustment During Pregnancy 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Life-Threatening Respiratory Depression 5.2 Life-Threatening QT Prolongation 5.3 Accidental Exposure 5.4 Abuse Potential 5.5 Elderly, Cachectic, and Debilitated Patients 5.6 Use in Patients with Chronic Pulmonary Disease 5.7 Interactions with CNS Depressants and Illicit Drugs 5.8 Hypotensive Effect 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure 5.10 Use in Patients with Gastrointestinal Conditions 5.11 Use in Patients with Convulsive or Seizure Disorders 5.12 Avoidance of Withdrawal 5.13 Driving and Operating Machinery 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 Cytochrome P450 Interactions 7.2 CNS Depressants 7.3 Potentially Arrhythmogenic Agents 7.4 Opioid Antagonists, Mixed Agonists/Antagonists, and Partial Agonists 7.5 Antidepressants 7.6 Anticholinergics 7.7 Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Neonatal Opioid Withdrawal Syndrome Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.7 Renal Impairment 8.8 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Storage and Handling 16.2 How Supplied 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT PROLONGATION, ACCIDENTAL EXPOSURE, ABUSE POTENTIAL and TREATMENT FOR OPIOID ADDICTION Life-threatening Respiratory Depression Respiratory depression, including fatal cases, have been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions (5.1)]. Proper dosing and titration are essential and DISKETS Dispersible Tablets should only be prescribed by healthcare professionals who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation of DISKETS Dispersible Tablets or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Life-Threatening QT Prolongation QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone [see Warnings and Precautions (5.2)]. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients for changes in cardiac rhythm during initiation and titration of DISKETS Dispersible Tablets. Accidental Exposure Accidental ingestion of DISKETS Dispersible Tablets, especially in children, can result in fatal overdose of methadone [see Warnings and Precautions (5.3)]. Abuse Potential DISKETS Dispersible Tablets contain methadone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions (5.4)]. Routinely monitor all patients receiving DISKETS for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence (9)]. Conditions For Distribution And Use Of Methadone Products For The Treatment of Opioid Addiction For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration [see Indications and Usage (1)]. INDICATIONS AND USAGE DISKETS Dispersible Tablets contain methadone, an opioid agonist indicated for the: • Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). • Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. Conditions For Distribution And Use Of Methadone Products For The Treatment Of Opioid Addiction Code of Federal Regulations, Title 42, Sec 8 Reference ID: 3376511 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Methadone products when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by opioid treatment programs (and agencies, practitioners or institutions by formal agreement with the program sponsor) certified by the Substance Abuse and Mental Health Services Administration and approved by the designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards (42 CFR 8.12). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment. Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval, and injunction precluding operation of the program. Regulatory Exceptions To The General Requirement For Certification To Provide Opioid Agonist Treatment: During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis. During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21CFR 1306.07(b)). 2 DOSAGE AND ADMINISTRATION Consider the following important factors that differentiate methadone from other opioids: • The peak respiratory depressant effect of methadone occurs later and persists longer than its peak pharmacologic effect. • A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other opioid agonists. • There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population- based conversion ratios between methadone and other opioids are not accurate when applied to individuals. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. • Steady-state plasma concentrations are not attained until 3 to 5 days after initiation of dosing. • Methadone has a narrow therapeutic index, especially when combined with other drugs. 2.1 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration. DISKETS are intended for dispersion in a liquid immediately prior to oral administration of the prescribed dose. The tablets should not be chewed or swallowed before dispersing in liquid. DISKETS are cross-scored, allowing for flexible dosage adjustment. Each cross-scored tablet may be broken or cut in half to yield two 20 mg doses, or in quarters to yield four 10-mg doses. Prior to administration, the desired dose of DISKETS should be dispersed in approximately 120 mL (4 ounces) of water, orange juice, or other acidic fruit beverage prior to taking. Methadone hydrochloride is very soluble in water, but there are some insoluble excipients that will not entirely dissolve. If residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture administered to the patient. Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg. To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of methadone if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (i.e., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Because DISKETS can be administered only in 10 mg increments, DISKETS may not be the appropriate product for initial dosing in many patients. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate. Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use. Also consider concurrent medications and the general condition and medical status of the patient when selecting the initial dose. Short-term Detoxification For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of methadone. Decrease the dose of methadone on a daily basis or at 2-day intervals, keeping the amount of methadone sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule. Because DISKETS can be administered only in 10 mg increments, DISKETS may not be the appropriate product for gradual dose reduction in many patients. 2.2 Titration and Maintenance Treatment of Opioid Dependence Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day. 2.3 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Because DISKETS can be administered only in 10 mg increments, it may not be the appropriate product for gradual dose reduction in many patients. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment. 2.4 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda illicit drug use in susceptible patients. 2.5 Considerations for Management of Acute Pain During Methadone Maintenance Treatment Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone. 2.6 Dosage Adjustment During Pregnancy Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. 3 DOSAGE FORMS AND STRENGTHS Each 40 mg d i sp er si b l e tablet for oral administration following dispersion in a liquid contains: 40 mg of methadone hydrochloride and is a p i llo w -sh ap e d , lig h t -p i nk i s h or a ng e c o m p r ess ed d i sp er s i b l e tablet. DISKETS are cross-scored, allowing for flexible dosage adjustment. Each tablet may be broken or cut in half to yield two 20-mg doses, or in quarters to yield four 10-mg doses. 4 CONTRAINDICATIONS DISKETS Dispersible Tablets are contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected paralytic ileus • Hypersensitivity (e.g. anaphylaxis) to methadone or any other ingredient in DISKETS Dispersible Tablets [see Adverse Reactions (6)] 5 WARNINGS AND PRECAUTIONS DISKETS Dispersible Tablets are for oral administration only. The preparation must not be injected. Methadone should be kept out of reach of children to prevent accidental ingestion. 5.1 Life-Threatening Respiratory Depression Respiratory depression is the primary risk of methadone. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid- induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of methadone, the risk is greatest during the initiation of therapy or following a dose increase. The peak Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Closely monitor patients with respiratory depression when initiating therapy with methadone and following dose increases. Instruct patients against use by individuals other than the patient for whom methadone was prescribed and to keep methadone out of the reach of children, as such inappropriate use may result in fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential [see Dosage and Administration (2.1)]. Overestimating the methadone dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of methadone when used as recommended and not misused or abused. To further reduce the risk of respiratory depression, consider the following: • Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross- tolerance is of particular concern for patients tolerant to other mu-opioid agonists who are being converted to treatment with methadone, thus making determination of dosing during opioid treatment conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. • Proper dosing and titration are essential and methadone should be prescribed only by healthcare professionals who are knowledgeable in the pharmacokinetics and pharmacodynamics of methadone. • Methadone is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications (4)]. 5.2 Life-Threatening QT Prolongation Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most patients on the lower doses typically used for maintenance, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. The effects of methadone on the QT interval have been confirmed in in vivo laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in in vitro studies. Closely monitor patients with risk factors for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone. Evaluate patients developing QT prolongation while on DISKETS Dispersible Tablets treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism. Only initiate therapy with DISKETS Dispersible Tablets in patients for whom the anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias that have been reported with high doses of methadone. The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied. Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.3 Accidental Exposure Accidental ingestion of DISKETS Dispersible Tablets, especially in children, can result in a fatal overdose of methadone. DISKETS Dispersible Tablets should be kept out of reach of children to prevent accidental ingestion. 5.4 Abuse Potential DISKETS Dispersible Tablets contain methadone, an opioid agonist and a Schedule II controlled substance. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.5 Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating DISKETS Dispersible Tablets and when DISKETS Dispersible Tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.1)]. 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with DISKETS Dispersible Tablets, as in these patients, even usual therapeutic doses of methadone may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.1)]. 5.7 Interactions with CNS Depressants and Illicit Drugs Hypotension, profound sedation, coma, or respiratory depression may result if methadone is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of DISKETS Dispersible Tablets in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If methadone therapy is to be initiated in a patient taking a CNS depressant, start with a lower methadone dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.2)]. Deaths associated with illicit use of methadone have frequently involved concomitant benzodiazepine abuse. 5.8 Hypotensive Effect Methadone may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain normal blood pressure is compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7.2)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of DISKETS Dispersible Tablets. Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking DISKETS Dispersible Tablets who may be susceptible to the intracranial effects of CO2 retention (e.g. those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with methadone. Methadone may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of methadone in patients with impaired consciousness or coma. 5.10 Use in Patients with Gastrointestinal Conditions DISKETS Dispersible Tablets are contraindicated in patients with paralytic ileus. Avoid the use of DISKETS Dispersible Tablets in patients with other gastrointestinal obstruction. Methadone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.11 Use in Patients with Convulsive or Seizure Disorders Methadone may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during DISKETS Dispersible Tablets therapy. 5.12 Avoidance of Withdrawal Avoid the use of partial agonists or mixed agonist/antagonist analgesics (i.e., buprenorphine, pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including methadone. In these patients, partial agonists or mixed agonists/antagonists analgesics may precipitate withdrawal symptoms [see Drug Interactions (7.4)]. When discontinuing DISKETS Dispersible Tablets, gradually taper the dose [see Dosage and Administration (2.3, 2.4)]. Do not abruptly discontinue DISKETS Dispersible Tablets. 5.13 Driving and Operating Machinery Methadone may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of DISKETS Dispersible Tablets and know how they will react to the medication. 6 ADVERSE REACTIONS The following adverse reactions have been identified during post-approval use of methadone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following serious adverse reactions and/or conditions are discussed elsewhere in the labeling: • Respiratory Depression [see Warnings and Precautions (5.1)] • QT Prolongation [see Warnings and Precautions (5.2)] • Chronic Pulmonary Disease [see Warnings and Precautions (5.6)] • Interactions with CNS Depressants [see Warnings and Precautions (5.7)] Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Hypotensive Effect [see Warnings and Precautions (5.8)] • Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions (5.9)] • Gastrointestinal Effects [see Warnings and Precautions (5.10)] • Seizures [see Warnings and Precautions (5.11)] The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, and death have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable. Other adverse reactions include the following: Body as a Whole: asthenia (weakness), edema, headache Cardiovascular: arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T- wave inversion, tachycardia, torsade de pointes, ventricular fibrillation, ventricular tachycardia Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances Endocrine: hypogonadism Gastrointestinal: abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis Hematologic: reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis Metabolic: hypokalemia, hypomagnesemia, weight gain Musculoskeletal: decreased muscle mass and strength, osteoporosis and fractures Renal: antidiuretic effect, urinary retention or hesitancy Reproductive: amenorrhea, reduced libido and/or potency, reduced ejaculate volume, reduced seminal vesicle and prostate secretions, decreased sperm motility, abnormalities in sperm morphology Respiratory: pulmonary edema, respiratory depression Skin and Subcutaneous Tissue: pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticaria Hypersensitivity: Anaphylaxis has been reported with ingredients contained in DISKETS Dispersible Tablets. Advise patients how to recognize such a reaction and when to seek medical attention. Maintenance on a Stabilized Dose: During prolonged administration of methadone, as in a methadone maintenance treatment program, constipation and sweating often persist and hypogonadism, decreased serum testosterone and reproductive effects are thought to be related to chronic opioid use. DISKETS Dispersible Tablets for the Detoxification and Maintenance Treatment of Opioid Dependence Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda During the induction phase of methadone maintenance treatment, patients are being withdrawn from illicit opioids and may have opioid withdrawal symptoms. Monitor patients for signs and symptoms including: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilling alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss and consider dose adjustment as indicated. 7 DRUG INTERACTIONS 7.1 Cytochrome P450 Interactions Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6 [see Clinical Pharmacology (12.3)]. Cytochrome P450 Inducers Concurrent use of methadone and drugs that induce cytochrome P450 enzymes (such as rifampicin, phenytoin, phenobarbital, carbamazepine, and St. John’s Wort) may result in reduced efficacy of methadone and could precipitate a withdrawal syndrome. Closely monitor patients receiving DISKETS Dispersible Tablets and an enzyme inducer closely for signs of withdrawal and adjust the methadone dose accordingly. Cytochrome P450 Inhibitors Coadministration of drugs that inhibit CYP3A4 (such as ketoconazole, itraconazole, voriconazole, clarithromycin, erythromycin, telithromycin) and/or drugs that inhibit CYP2C9 (such as sertraline and fluvoxamine) may cause decreased clearance of methadone, which could increase or prolong adverse drug effects and may cause fatal respiratory depression [see Clinical Pharmacology (12.3)]. Monitor patients closely for signs of respiratory or central nervous system depression when DISKETS Dispersible Tablets are prescribed with a CYP3A4 inhibitor and reduce the dosage if necessary. Paradoxical Effects of Antiretroviral Agents on Methadone Concurrent use of certain protease inhibitors with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of DISKETS Dispersible Tablets and could precipitate a withdrawal syndrome. Monitor patients receiving DISKETS Dispersible Tablets and any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the DISKETS Dispersible Tablets dose accordingly. Effects of Methadone on Antiretroviral Agents Didanosine and Stavudine: Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered. Zidovudine: Experimental evidence demonstrated that methadone increased the AUC of zidovudine, which could result in toxic effects. 7.2 CNS Depressants Concurrent use of methadone and other central nervous system (CNS) depressants (e.g. sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers, alcohol and drugs of abuse) can increase the risk of respiratory depression, hypotension, and profound sedation or coma. Monitor patients receiving CNS depressants and DISKETS Dispersible Tablets for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents. Deaths have been reported Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda when methadone has been abused in conjunction with benzodiazepines. 7.3 Potentially Arrhythmogenic Agents Monitor patients closely for cardiac conduction changes when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with DISKETS Dispersible Tablets. Pharmacodynamic interactions may occur with concomitant use of DISKETS Dispersible Tablets and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Similarly, monitor patients closely when prescribing DISKETS Dispersible Tablets concomitantly with drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval, including diuretics, laxatives, and, in rare cases, mineralocorticoid hormones. 7.4 Opioid Antagonists, Mixed Agonist/Antagonists, and Partial Agonists As with other mu-agonists, patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists. Examples of such agents are naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine. 7.5 Antidepressants Monoamine Oxidase (MAO) Inhibitors: Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone. However, if the use of DISKETS Dispersible Tablets is necessary in such patients, a sensitivity test should be performed in which repeated small, incremental doses of DISKETS Dispersible Tablets are administered over the course of several hours while the patient’s condition and vital signs are carefully observed. Desipramine: Blood levels of desipramine have increased with concurrent methadone administration. 7.6 Anticholinergics Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioids may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when DISKETS Dispersible Tablets are used concurrently with anticholinergic drugs. 7.7 Laboratory Test Interactions False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramaine, chlorpromazine, thioridazine, quetiapine, and verapamil. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well controlled studies of methadone use in pregnant women. Methadone has been shown to be teratogenic in the hamster at doses 2 times the human daily oral dose (120 mg/day on a mg/m2 basis) and in mice at doses equivalent to the human daily oral dose (120 mg/day on a mg/m2 basis). Increased neonatal mortality and significant differences in behavioral tests have been reported in the offspring of male Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda rodents that were treated with methadone prior to mating when compared to control animals. Methadone has been detected in human amniotic fluid and cord plasma at concentrations proportional to maternal plasma and in newborn urine at lower concentrations than corresponding maternal urine. DISKETS Dispersible Tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Dosage Adjustment During Pregnancy The disposition of oral methadone has been studied in approximately 30 pregnant patients in 2nd and 3rd trimesters. Total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women. The terminal half-life of methadone is decreased during 2nd and 3rd trimesters. The decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may need to be increased or the dosing interval decreased in pregnant patients receiving DISKETS Dispersible Tablets to achieve therapeutic effect [see Dosage and Administration (2.6)]. Effect on the Neonate Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. Onset of withdrawal symptoms in infants is usually in the first days after birth. Monitor newborn for withdrawal signs and symptoms including: irritability and excessive crying, tremors, hyper-active reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the neonatal withdrawal syndrome does not always correlate with the maternal dose or the duration of maternal exposure. The duration of the withdrawal signs may vary from a few days to weeks or even months. There is no consensus on the appropriate management of infant withdrawal [see Use in Specific Populations (8.6)]. Human Data Reported studies have generally compared the benefit of methadone to the risk of untreated addiction to illicit drugs. Pregnant women involved in methadone maintenance programs have been reported to have significantly improved prenatal care leading to significantly reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Several factors, including maternal use of illicit drugs, nutrition, infection and psychosocial circumstances, complicate the interpretation of investigations of the children of women who take methadone during pregnancy. Information is limited regarding dose and duration of methadone use during pregnancy, and most maternal exposure appears to occur after the first trimester of pregnancy. A review of published data on experiences with methadone use during pregnancy by the Teratogen Information System (TERIS) concluded that maternal use of methadone during pregnancy as part of a supervised, therapeutic regimen is unlikely to pose a substantial teratogenic risk (quantity and quality of data assessed as “limited to fair”). However, the data are insufficient to state that there is no risk (TERIS, last reviewed October, 2002). A retrospective case series of 101 pregnant, opioid-dependent women who underwent inpatient opiate detoxification with methadone did not demonstrate any increased risk of miscarriage in the 2nd trimester or premature delivery in the 3rd trimester. Recent studies suggest an increased risk of premature delivery in opioid-dependent women exposed to methadone during pregnancy, although the presence of confounding factors makes it difficult to determine a causal relationship. Several studies have suggested that infants born to narcotic-addicted women treated with methadone during all or part of pregnancy have been found to have decreased fetal growth with reduced birth weight, length, and/or head circumference compared to controls. This growth deficit does not appear to persist into later childhood. Children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests. In addition, several studies suggest that children born to opioid-dependent women exposed to methadone during pregnancy may have an increased risk of visual development anomalies; however, a casual relationship has not been assigned. There are conflicting reports on whether Sudden Infant Death Syndrome occurs with an increased incidence in Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda infants born to women treated with methadone during pregnancy. Abnormal fetal non-stress tests have been reported to occur more frequently when the test is performed 1 to 2 hours after a maintenance dose of methadone in late pregnancy compared to controls. Animal Data Methadone did not produce teratogenic effects in rat or rabbit models. Methadone produced teratogenic effects following large doses, in the guinea pig, hamster, and mouse. One published study in pregnant hamsters indicated that a single subcutaneous dose of methadone ranging from 31 to 185 mg/kg (the 31 mg/kg dose is approximately 2 times a human daily oral dose of 120 mg/day on a mg/m2 basis) on day 8 of gestation resulted in a decrease in the number of fetuses per litter and an increase in the percentage of fetuses exhibiting congenital malformations described as exencephaly, cranioschisis, and “various other lesions.” The majority of the doses tested also resulted in maternal death. In another study, a single subcutaneous dose of 22 to 24 mg/kg methadone (estimated exposure was approximately equivalent to a human daily oral dose of 120 mg/day on a mg/m2 basis) administered on day 9 of gestation in mice also produced exencephaly in 11% of the embryos. However, no effects were reported in rats and rabbits at oral doses up to 40 mg/kg (estimated exposure was approximately 3 and 6 times, respectively, a human daily oral dose of 120 mg/day on a mg/m2 basis) administered during days 6 to 15 and 6 to 18, respectively. Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone prior to mating. In these studies, the female rodents were not treated with methadone, indicating paternally-mediated developmental toxicity. Specifically, methadone administered to the male rat prior to mating with methadone-naïve females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. Behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals, suggesting that paternal methadone exposure can produce physiological and behavioral changes in progeny in this model. Other animal studies have reported that perinatal exposure to opioids including methadone alters neuronal development and behavior in the offspring. Perinatal methadone exposure in rats has been linked to alterations in learning ability, motor activity, thermal regulation, nociceptive responses and sensitivity to drugs. Additional animal data demonstrates evidence for neurochemical changes in the brains of methadone-treated offspring, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems. Studies demonstrated that methadone treatment of male rats for 21 to 32 days prior to mating with methadone-naïve females did not produce any adverse effects, suggesting that prolonged methadone treatment of the male rat resulted in tolerance to the developmental toxicities noted in the progeny. Mechanistic studies in this rat model suggest that the developmental effects of “paternal” methadone on the progeny appear to be due to decreased testosterone production. These animal data mirror the reported clinical findings of decreased testosterone levels in human males on methadone maintenance therapy for opioid addiction and in males receiving chronic intraspinal opioids. Additional data have been published indicating that methadone treatment of male rats (once a day for three consecutive days) increased embryolethality and neonatal mortality. Examination of uterine contents of methadone-naive female mice bred to methadone-treated mice indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states. 8.2 Labor and Delivery Methadone is not for use in women during and immediately prior to labor. Opioid analgesics may prolong labor by temporarily reducing the strength, duration and frequency of uterine contractions. However, these effects are not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Opioids with mixed agonist-antagonist properties should not be used for pain control during labor in patients chronically treated with methadone as they may precipitate acute withdrawal [see Drug Interactions (7.4)]. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate. 8.3 Nursing Mothers Methadone is secreted into human milk. At maternal oral doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk have been reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone. Cases of sedation and respiratory depression in infants exposed to methadone through breast milk have been reported. Caution should be exercised when DISKETS Dispersible Tablets are administered to a nursing woman. Advise women who are being treated with DISKETS Dispersible Tablets and who are breastfeeding or express a desire to breastfeed of the presence of methadone in human milk. Instruct breastfeeding mothers how to identify respiratory depression and sedation in their babies and when it may be necessary to contact their healthcare provider or seek immediate medical care. Breastfed infants of mothers using methadone should be weaned gradually to prevent development of withdrawal symptoms in the infant. 8.4 Pediatric Use The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established. 8.5 Geriatric Use Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, start elderly at the low end of the dosing range, taking into account the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients. Closely monitor elderly patients for signs of respiratory and central nervous system depression. 8.6 Neonatal Opioid Withdrawal Syndrome Chronic maternal use of methadone during pregnancy can affect the fetus with subsequent withdrawal signs. Neonatal withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration and severity of neonatal withdrawal syndrome vary based on the drug used, duration of use, the dose of last maternal use, and rate of elimination drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts. Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.7 Renal Impairment Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression. 8.8 Hepatic Impairment Methadone pharmacokinetics have not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized by hepatic pathways; therefore, patients with liver impairment may be at risk of increased systemic exposure to methadone after multiple dosing. Start these patients on lower doses and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methadone is a mu-agonist opioid with an abuse liability similar to other opioid agonists and is a Schedule II controlled substance. Methadone and other opioids have the potential for being abused and are subject to criminal diversion [see Warnings and Precautions (5.4)]. 9.2 Abuse Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of lost prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Methadone, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state law, is strongly advised. Abuse of methadone poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone with alcohol and other substances. DISKETS Dispersible Tablets are intended for oral use only and Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda must not be injected. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Proper assessment and selection of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. DISKETS Dispersible Tablets, when used for the treatment of opioid addiction in detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration (and agencies, practitioners, and institutions by formal agreements with the program sponsor). 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or significant dose reduction of a drug. Withdrawal is also precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Physical dependence is expected during opioid agonist therapy of opioid addiction. DISKETS Dispersible Tablets should not be abruptly discontinued [see Dosage and Administration (2.3, 2.4)]. If DISKETS Dispersible Tablets are abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids may also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.6)]. 10 OVERDOSAGE Clinical Symptoms Acute overdosage of methadone is manifested by respiratory depression, somnolence progressing to stupor or coma, maximally constricted pupils, skeletal-muscle flaccidity, cold and clammy skin, and sometimes, bradycardia and hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The opioid antagonists, such as naloxone, are available as specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda respiratory or circulatory depression secondary to methadone overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on methadone. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. Because the duration of reversal would be expected to be less than the duration of action of methadone, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product’s prescribing information. In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. 11 DESCRIPTION Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride. Methadone hydrochloride is a white, essentially odorless, bitter-tasting crystalline powder. It is very soluble in water, soluble in isopropranol and in chloroform, and practically insoluble in ether and in glycerine. It is present in DISKETS Dispersible Tablets as the racemic mixture. Methadone hydrochloride has a melting point of 235°C, a pKa of 8.25 in water at 20°C, a solution (1 part per 100) pH between 4.5 and 6.5, a partition coefficient of 117 at pH 7.4 in octanol/water and a molecular weight of 345.91. Its molecular formula is C21H27NO•HCl and its structural formula is: structural formula Each DISKETS Dispersible Tablet contains 40 mg of methadone hydrochloride, USP and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, orange lake color, orange- pineapple flavor, potassium phosphate monobasic, pregelatinized starch, and stearic acid. DISKETS Dispersible Tablets are cross-scored, allowing for flexible dosage adjustment. Each tablet may be broken or cut in half to yield two 20-mg doses, or in quarters to yield four 10-mg doses. DISKETS Dispersible Tablets (Methadone Hydrochloride Tablets for Oral Suspension, USP), are for oral administration following dispersion in a liquid. DISKETS Dispersible Tablets contain insoluble excipients and must not be injected. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methadone hydrochloride is a mu-agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda composed of smooth muscle. The methadone withdrawal syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals. 12.3 Pharmacokinetics Absorption Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 to 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated. Distribution Methadone is a lipophilic drug and the steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 90%). Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma. Metabolism Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl 3,3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the urine. Methadone appears to be a substrate for P glycoprotein but its pharmacokinetics do not appear to be significantly altered in case of P-glycoprotein polymorphism or inhibition. Excretion The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Published reports indicate that after multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 and 126 L/h, and the terminal half-life (T1/2) was highly variable and ranged between 8 to 59 hours in different studies. Methadone is a basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in plasma. Also, since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations. Drug Interactions Cytochrome P450 Interactions Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with CYP inducers may result in more rapid metabolism and potential for decreased effects of methadone, whereas administration with CYP inhibitors may reduce metabolism and potentiate methadone’s effects. Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to CYP induction activity [see Drug Interactions (7.1)]. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy. Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cytochrome P450 Inducers The following drug interactions were reported following coadministration of methadone with known inducers of cytochrome P450 enzymes: Rifampin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms. Phenytoin: In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg twice daily initially for 1 day followed by 300 mg daily for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin administration. St. John’s Wort, Phenobarbital, Carbamazepine: Administration of methadone with other CYP3A4 inducers may result in withdrawal symptoms. Cytochrome P450 Inhibitors Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. Voriconazole: Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the peak plasma concentration (Cmax) and AUC of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg daily). The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed [see Drug Interactions (7.1)]. Antiretroviral drugs: Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to CYP induction activity. Abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, tipranvir+ritonavir combination: Coadministration of these anti retroviral agents resulted in increased clearance or decreased plasma levels of methadone [see Drug Interactions (7.1)]. Didanosine and Stavudine: Methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered [see Drug Interactions (7.1)]. Zidovudine: Methadone increased the AUC of zidovudine which could result in toxic effects [see Drug Interactions (7.1)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis The results of carcinogenicity assessment in B6C2F1 mice and Fischer 344 rats following dietary administration of two doses of methadone HCl have been published. Mice consumed 15 mg/kg/day or 60 mg/kg/day Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda methadone for two years. These doses were approximately 0.6 and 2.5 times a human daily oral dose of 120 mg/day on a body surface area basis (mg/m2). There was a significant increase in pituitary adenomas in female mice treated with 15 mg/kg/day but not with 60 mg/kg/day. Under the conditions of the assay, there was no clear evidence for a treatment-related increase in the incidence of neoplasms in male rats. Due to decreased food consumption in males at the high dose, male rats consumed 16 mg/kg/day and 28 mg/kg/day of methadone for two years. These doses were approximately 1.3 and 2.3 times a human daily oral dose of 120 mg/day, based on body surface area comparison. In contrast, female rats consumed 46 mg/kg/day or 88 mg/kg/day for two years. These doses were approximately 3.7 and 7.1 times a human daily oral dose of 120 mg/day, based on body surface area comparison. Under the conditions of the assay, there was no clear evidence for a treatment-related increase in the incidence of neoplasms in either male or female rats. Mutagenesis There are several published reports on the potential genetic toxicity of methadone. Methadone tested positive in the in vivo mouse dominant lethal assay and the in vivo mammalian spermatogonial chromosome aberration test. Additionally, methadone tested positive in the E. coli DNA repair system and Neurospora crassa and mouse lymphoma forward mutation assays. In contrast, methadone tested negative in tests for chromosome breakage and disjunction and sex-linked recessive lethal gene mutations in germ cells of Drosophila using feeding and injection procedures. Fertility Published animal studies show that methadone treatment of males can alter reproductive function. Methadone produces a significant regression of sex accessory organs and testes of male mice and rats. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Storage and Handling DISKETS Dispersible Tablets contain methadone which is a controlled substance. Like fentanyl, morphine, oxycodone, hydromorphone, and oxymorphone, methadone is controlled under Schedule II of the Federal Controlled Substances Act. DISKETS Dispersible Tablets may be targeted for theft and diversion by criminals [see Warnings and Precautions (5.4)]. DISKETS Dispersible Tablets, if dispensed, must be packaged in child-resistant containers and kept out of reach of children to prevent accidental ingestion. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. 16.2 How Supplied DISKETS Dispersible Tablets (Methadone Hydrochloride Tablets for Oral Suspension, USP) 40 mg Tablets: peach, cross-scored tablets (Identified 54 883) NDC 0054-4538-25: Bottles of 100 dispersible tablets. DEA order form required. Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 PATIENT COUNSELING INFORMATION Provide the following information to patients receiving DISKETS Dispersible Tablets or their caregivers: Life-Threatening Respiratory Depression Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting DISKETS Dispersible Tablets or when the dose is increased. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties. Symptoms of Arrhythmia Instruct patients to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (such as palpitations, near syncope, or syncope) when taking DISKETS Dispersible Tablets. Accidental Exposure Instruct patients to take steps to store DISKETS Dispersible Tablets securely. Accidental ingestion especially in children, may result in serious harm or death. Advise patients to dispose of unused DISKETS Dispersible Tablets by flushing the tablets down the toilet. Abuse Potential Inform patients that DISKETS Dispersible Tablets contain methadone, a Schedule II controlled substance that is subject to abuse. Instruct patients not to share DISKETS Dispersible Tablets with others and to take steps to protect DISKETS Dispersible Tablets from theft or misuse. Risks from Concomitant Use of Alcohol and other CNS Depressants Inform patients that the concomitant use of alcohol with methadone can increase the risk of life-threatening respiratory depression. Instruct patients not to consume alcoholic beverages, as well as prescription and over the-counter drug products that contain alcohol, during treatment with DISKETS Dispersible Tablets. Inform patients that potentially serious additive effects may occur if methadone is used with other CNS depressants, and not to use such drugs unless supervised by a health care provider. Important Administration Instructions Instruct patients how to properly take DISKETS Dispersible Tablets, including the following: • DISKETS Dispersible Tablets are for oral administration only and must be initially dispersed in liquid before use. After dispersion in liquid, the preparation must not be injected. • Inform patients that DISKETS Dispersible Tablets should be taken only as directed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression), and the dose should not be adjusted without consulting a physician or other healthcare professional. • Reassure patients initiating treatment with DISKETS Dispersible Tablets for opioid dependence that the dose of methadone will “hold” for longer periods of time as treatment progresses. • Apprise patients seeking to discontinue treatment with methadone for opioid dependence of the high risk of relapse to illicit drug use associated with discontinuation of DISKETS Dispersible Tablets maintenance treatment. • Advise patients not to discontinue DISKETS Dispersible Tablets without first discussing the need for a tapering regimen with the prescriber. Hypotension Inform patients that DISKETS Dispersible Tablets may cause orthostatic hypotension and syncope. Instruct patients on how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Driving or Operating Heavy Machinery Inform patients that DISKETS Dispersible Tablets may impair the ability to perform potentially hazardous activities such as driving or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in DISKETS Dispersible Tablets. Advise patients how to recognize such a reaction and when to seek medical attention. Pregnancy Advise female patients that DISKETS Dispersible Tablets can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant. Breastfeeding Instruct nursing mothers using DISKETS Dispersible Tablets to watch for signs of methadone toxicity in their infants, which include increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to their baby’s healthcare provider immediately if they notice these signs. If they cannot reach the healthcare provider right away, instruct them to take the baby to the emergency room or call 911 (or local emergency services). 10005657/02 company logo Reference ID: 3376511 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:07.666734	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017058s021lbl.pdf', 'application_number': 17058, 'submission_type': 'SUPPL ', 'submission_number': 21}
10,957	1 DX:L57 PRESCRIBING INFORMATION DEXEDRINE® (dextroamphetamine sulfate) SPANSULE® sustained-release capsules and Tablets WARNING AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINES MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS. DESCRIPTION DEXEDRINE (dextroamphetamine sulfate) is the dextro isomer of the compound d,l-amphetamine sulfate, a sympathomimetic amine of the amphetamine group. Chemically, dextroamphetamine is d-alpha-methylphenethylamine, and is present in all forms of DEXEDRINE as the neutral sulfate. Structural formula: SPANSULE capsules: Each SPANSULE sustained-release capsule is so prepared that an initial dose is released promptly and the remaining medication is released gradually over a prolonged period. Each capsule, with brown cap and clear body, contains dextroamphetamine sulfate. The 5-mg capsule is imprinted 5 mg and 3512 on the brown cap and is imprinted 5 mg and SB on the clear body. The 10-mg capsule is imprinted 10 mg—3513—on the brown cap and is imprinted 10 mg—SB—on the clear body. The 15-mg capsule is imprinted 15 mg and 3514 on the brown cap and is imprinted 15 mg and SB on the clear body. A narrow bar appears above and below 15 mg and 3514. Product reformulation in 1996 has caused a minor change in the color of the time-released pellets within each capsule. Inactive ingredients now consist of cetyl alcohol, D&C This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Yellow No. 10, dibutyl sebacate, ethylcellulose, FD&C Blue No. 1, FD&C Blue No. 1 aluminum lake, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, hypromellose, propylene glycol, povidone, silicon dioxide, sodium lauryl sulfate, sugar spheres, and trace amounts of other inactive ingredients. Tablets: Each triangular, orange, scored tablet is debossed SKF and E19 and contains dextroamphetamine sulfate, 5 mg. Inactive ingredients consist of calcium sulfate, FD&C Yellow No. 5 (tartrazine), FD&C Yellow No. 6, gelatin, lactose, mineral oil, starch, stearic acid, sucrose, talc, and trace amounts of other inactive ingredients. CLINICAL PHARMACOLOGY Amphetamines are noncatecholamine, sympathomimetic amines with CNS stimulant activity. Peripheral actions include elevations of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant action. There is neither specific evidence that clearly establishes the mechanism whereby amphetamines produce mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. DEXEDRINE SPANSULE capsules are formulated to release the active drug substance in vivo in a more gradual fashion than the standard formulation, as demonstrated by blood levels. The formulation has not been shown superior in effectiveness over the same dosage of the standard, noncontrolled-release formulations given in divided doses. Pharmacokinetics: The pharmacokinetics of the tablet and sustained-release capsule were compared in 12 healthy subjects. The extent of bioavailability of the sustained-release capsule was similar compared to the immediate-release tablet. Following administration of three 5-mg tablets, average maximal dextroamphetamine plasma concentrations (Cmax) of 36.6 ng/mL were achieved at approximately 3 hours. Following administration of one 15-mg sustained-release capsule, maximal dextroamphetamine plasma concentrations were obtained approximately 8 hours after dosing. The average Cmax was 23.5 ng/mL. The average plasma T½ was similar for both the tablet and sustained-release capsule and was approximately 12 hours. In 12 healthy subjects, the rate and extent of dextroamphetamine absorption were similar following administration of the sustained-release capsule formulation in the fed (58 to 75 gm fat) and fasted state. INDICATIONS AND USAGE DEXEDRINE is indicated in: Narcolepsy Attention Deficit Disorder with Hyperactivity: As an integral part of a total treatment program that typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in pediatric patients (ages 3 years to 16 years) with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: Moderate to severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. CONTRAINDICATIONS Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated states. Patients with a history of drug abuse. During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death in Patients with Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems: Children and Adolescents: Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults: Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS). Hypertension and Other Cardiovascular Conditions: Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS). Assessing Cardiovascular Status in Patients Being Treated With Stimulant Medications: Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis: Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness: Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms: Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression: Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of, or worsening of, aggressive behavior or hostility. Long-Term Suppression of Growth: Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.Seizures: There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Visual Disturbance: Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. PRECAUTIONS General: The least amount feasible should be prescribed or dispensed at 1 time in order to minimize the possibility of overdosage. The tablets contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Information for Patients: Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. Drug Interactions: Acidifying agents: Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines. Urinary acidifying agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines. Adrenergic blockers: Adrenergic blockers are inhibited by amphetamines. Alkalinizing agents: Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines. Antidepressants, tricyclic: Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. MAO inhibitors: MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results. Antihistamines: Amphetamines may counteract the sedative effect of antihistamines. Antihypertensives: Amphetamines may antagonize the hypotensive effects of antihypertensives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Chlorpromazine: Chlorpromazine blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning. Ethosuximide: Amphetamines may delay intestinal absorption of ethosuximide. Haloperidol: Haloperidol blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines. Lithium carbonate: The stimulatory effects of amphetamines may be inhibited by lithium carbonate. Meperidine: Amphetamines potentiate the analgesic effect of meperidine. Methenamine therapy: Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy. Norepinephrine: Amphetamines enhance the adrenergic effect of norepinephrine. Phenobarbital: Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin: Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene: In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur. Veratrum alkaloids: Amphetamines inhibit the hypotensive effect of veratrum alkaloids. Drug/Laboratory Test Interactions: Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations. Carcinogenesis/Mutagenesis: Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of DEXEDRINE have not been performed. Pregnancy: Teratogenic Effects: Pregnancy Category C. DEXEDRINE has been shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses approximately 41 times the maximum human dose. Embryotoxic effects were not seen in New Zealand white rabbits given the drug in doses 7 times the human dose nor in rats given 12.5 times the maximum human dose. While there are no adequate and well-controlled studies in pregnant women, there has been 1 report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. DEXEDRINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude. Nursing Mothers: Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Pediatric Use: Long-term effects of amphetamines in pediatric patients have not been well established. Amphetamines are not recommended for use in pediatric patients under 3 years of age with Attention Deficit Disorder with Hyperactivity described under INDICATIONS AND USAGE. Clinical experience suggests that in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder. Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications. Data are inadequate to determine whether chronic administration of amphetamines may be associated with growth inhibition; therefore, growth should be monitored during treatment. Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe amphetamines should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his or her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with amphetamines is usually not indicated. ADVERSE REACTIONS Cardiovascular: Palpitations, tachycardia, elevation of blood pressure. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Psychotic episodes at recommended doses (rare), overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonic tics, and Tourette’s syndrome. Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic: Urticaria. Endocrine: Impotence, changes in libido. DRUG ABUSE AND DEPENDENCE Dextroamphetamine sulfate is a Schedule II controlled substance. Amphetamines have been extensively abused. Tolerance, extreme psychological dependence and severe social disability have occurred. There are reports of patients who have increased the dosage to many times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. This is rare with oral amphetamines. OVERDOSAGE Individual patient response to amphetamines varies widely. While toxic symptoms occasionally occur as an idiosyncrasy at doses as low as 2 mg, they are rare with doses of less than 15 mg; 30 mg can produce severe reactions, yet doses of 400 to 500 mg are not necessarily fatal. In rats, the oral LD50 of dextroamphetamine sulfate is 96.8 mg/kg. Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rhabdomyolysis, rapid respiration, hyperpyrexia, confusion, assaultiveness, hallucinations, panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. TREATMENT Consult with a Certified Poison Control Center for up-to-date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic, and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute, severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine (Bedford Laboratories) has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication. Since much of the SPANSULE capsule medication is coated for gradual release, therapy directed at reversing the effects of the ingested drug and at supporting the patient should be continued for as long as overdosage symptoms remain. Saline cathartics are useful for hastening the evacuation of pellets that have not already released medication. DOSAGE AND ADMINISTRATION Amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted. Late evening doses—particularly with the SPANSULE capsule form— should be avoided because of the resulting insomnia. Narcolepsy: Usual dose is 5 to 60 mg per day in divided doses, depending on the individual patient response. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Narcolepsy seldom occurs in children under 12 years of age; however, when it does, DEXEDRINE may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until an optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until an optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. SPANSULE capsules may be used for once-a-day dosage wherever appropriate. With tablets, give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours. Attention Deficit Disorder with Hyperactivity: Not recommended for pediatric patients under 3 years of age. In pediatric patients from 3 to 5 years of age, start with 2.5 mg daily, by tablet; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained. In pediatric patients 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. SPANSULE capsules may be used for once-a-day dosage wherever appropriate. With tablets, give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours. Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. HOW SUPPLIED DEXEDRINE SPANSULE capsules: Each capsule, with brown cap and clear body, contains dextroamphetamine sulfate. The 5-mg capsule is imprinted 5 mg and 3512 on the brown cap and is imprinted 5 mg and SB on the clear body. The 10-mg capsule is imprinted 10 mg—3513—on the brown cap and is imprinted 10 mg—SB—on the clear body. The 15-mg capsule is imprinted 15 mg and 3514 on the brown cap and is imprinted 15 mg and SB on the clear body. A narrow bar appears above and below 15 mg and 3514. Available: 5 mg, 10 mg, and 15 mg in bottles of 100. DEXEDRINE SPANSULE capsules are manufactured by Cardinal Health, Winchester, KY 40391. Store at controlled room temperature between 20° and 25°C (68° and 77°F) [see USP]. Dispense in a tight, light-resistant container. 5 mg 100s: NDC 0007-3512-20 10 mg 100s: NDC 0007-3513-20 15 mg 100s: NDC 0007-3514-20 DEXEDRINE Tablets: Triangular, orange, scored, debossed SKF and E19. Available: 5 mg in bottles of 100. DEXEDRINE Tablets are manufactured by Abbott Laboratories, North Chicago, IL 60064. Store between 15° and 30°C (59° and 86°F). Dispense in a tight, light-resistant container. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 5 mg 100s: NDC 0007-3519-20 GlaxoSmithKline Research Triangle Park, NC 27709 ©2006, GlaxoSmithKline. All rights reserved. June 2006 DX:L57 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:07.704350	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017078s040lbl.pdf', 'application_number': 17078, 'submission_type': 'SUPPL ', 'submission_number': 40}
10,958	DEXEDRINE® (dextroamphetamine sulfate) SPANSULE® sustained release capsules Cll Rx Only WARNING: AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINES MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS. DESCRIPTION: DEXEDRINE (dextroamphetamine sulfate) is the dextro isomer of the compound d,1-amphetamine sulfate, a sympathomimetic amine of the amphetamine group. Chemically, dextroamphetamine is d-alpha-methylphenethylamine, and is present in all forms of DEXEDRINE as the neutral sulfate. Structural formula: structural formula SPANSULE capsules: Each SPANSULE sustained-release capsule is so prepared that an initial dose is released promptly and the remaining medication is released gradually over a prolonged period. Each capsule, with brown cap and clear body, contains dextroamphetamine sulfate. The 5-mg capsule is imprinted 5 mg and 512 on the brown cap and is imprinted 5 mg and ap on the clear body. The 10-mg capsule is imprinted 10 mg—513—on the brown cap and is imprinted 10 mg—ap—on the clear body. The 15-mg capsule is imprinted 15 mg and 514 on the brown cap and is imprinted 15 mg and ap on the clear body. A narrow bar appears above and below 15 mg and 514. Product reformulation in 1996 has caused a minor change in the color of the time-released pellets within each capsule. Inactive ingredients now consist of cetyl alcohol, D&C Yellow No. 10, dibutyl sebacate, ethylcellulose, FD&C Blue No. 1, FD&C Blue No. 1 aluminum lake, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, hypromellose, polyethylene glycol, povidone, sodium lauryl sulfate, sugar spheres, and trace amounts of other inactive ingredients. CLINICAL PHARMACOLOGY: Amphetamines are noncatecholamine, sympathomimetic amines with CNS stimulant activity. Peripheral actions include elevations of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant action. There is neither specific evidence that clearly establishes the mechanism whereby amphetamines produce mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. DEXEDRINE SPANSULE Capsules are formulated to release the active drug substance in vivo in a more gradual fashion than the standard formulation, as demonstrated by blood levels. The formulation has not been shown superior in effectiveness over the same dosage of the standard, noncontrolled-release formulations given in divided doses. Pharmacokinetics: The pharmacokinetics of the tablet and sustained-release capsule were compared in 12 healthy subjects. The extent of bioavailability of the sustained-release capsule was similar compared to the immediate-release tablet. Following administration of three 5-mg tablets, average maximal dextroamphetamine plasma concentrations (Cmax) of 36.6 ng/mL were achieved at approximately 3 hours. Following administration of one 15-mg sustained-release capsule, maximal dextroamphetamine plasma concentrations were obtained approximately 8 hours after dosing. The average Cmax was 23.5 ng/mL. The average plasma T½ was similar for both the tablet and sustained-release capsule and was approximately 12 hours. In 12 healthy subjects, the rate and extent of dextroamphetamine absorption were similar following administration of the sustained-release capsule formulation in the fed (58 to 75 gm fat) and fasted state. INDICATIONS AND USAGE: DEXEDRINE is indicated in: Narcolepsy page 1 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attention Deficit Disorder with Hyperactivity As an integral part of a total treatment program that typically includes other measures (psychological, educational, social) for patients (ages 6 years to 16 years) with this syndrome. A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of the hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go”; excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presences of the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program DEXEDRINE is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Stimulants are not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms. CONTRAINDICATIONS Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated states. Patients with a history of drug abuse. During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death in Patients With Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS). Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS). page 2 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of, or worsening of, aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non- medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non- medication treated children older than 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Peripheral Vasculopathy, including Raynaud’s phenomenon Stimulants, including DEXEDRINE, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. page 3 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General The least amount feasible should be prescribed or dispensed at 1 time in order to minimize the possibility of overdosage. Information for Patients: Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with dextroamphetamine and should counsel them in its appropriate use. A patient Medication Guide is available for DEXEDRINE. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon] • Instruct patients beginning treatment with DEXEDRINE about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. • Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. • Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking DEXEDRINE. • Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Drug Interactions Acidifying Agents Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines. Urinary acidifying agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines. Adrenergic Blockers Adrenergic blockers are inhibited by amphetamines. Alkalinizing Agents Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines. Antidepressants, Tricyclic Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. MAO Inhibitors MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results. Antihistamines Amphetamines may counteract the sedative effect of antihistamines. Antihypertensives Amphetamines may antagonize the hypotensive effects of antihypertensives. Chlorpromazine Chlorpromazine blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines, and can page 4 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be used to treat amphetamine poisoning. Ethosuximide Amphetamines may delay intestinal absorption of ethosuximide. Haloperidol Haloperidol blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines. Lithium Carbonate The stimulatory effects of amphetamines may be inhibited by lithium carbonate. Meperidine Amphetamines potentiate the analgesic effect of meperidine. Methenamine Therapy Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy. Norepinephrine Amphetamines enhance the adrenergic effect of norepinephrine. Phenobarbital Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur. Veratrum Alkaloids Amphetamines inhibit the hypotensive effect of veratrum alkaloids. Drug/Laboratory Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations. Carcinogenesis/Mutagenesis Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of DEXEDRINE have not been performed. Pregnancy Teratogenic Effects Pregnancy Category C. DEXEDRINE has been shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses approximately 41 times the maximum human dose. Embryotoxic effects were not seen in New Zealand white rabbits given the drug in doses 7 times the human dose nor in rats given 12.5 times the maximum human dose. While there are no adequate and well-controlled studies in pregnant women, there has been 1 report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. DEXEDRINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude. Nursing Mothers Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing. Pediatric Use Long-term effects of amphetamines in pediatric patients have not been well established. DEXEDRINE is not recommended for use in pediatric patients younger than 6 years of age with Attention Deficit Disorder with Hyperactivity described under INDICATIONS AND USAGE. page 5 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical experience suggests that in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder. Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications. Data are inadequate to determine whether chronic administration of amphetamines may be associated with growth inhibition; therefore, growth should be monitored during treatment. Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe amphetamines should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his or her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with amphetamines is usually not indicated. ADVERSE REACTIONS Cardiovascular Palpitations, tachycardia, elevation of blood pressure. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System Psychotic episodes at recommended doses (rare), overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonic tics, and Tourette’s syndrome. Gastrointestinal Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic Urticaria. Endocrine Impotence, changes in libido. DRUG ABUSE AND DEPENDENCE Dextroamphetamine sulfate is a Schedule II controlled substance. Amphetamines have been extensively abused. Tolerance, extreme psychological dependence and severe social disability have occurred. There are reports of patients who have increased the dosage to many times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. This is rare with oral amphetamines. OVERDOSAGE Individual patient response to amphetamines varies widely. While toxic symptoms occasionally occur as an idiosyncrasy at doses as low as 2 mg, they are rare with doses of less than 15 mg; 30 mg can produce severe reactions, yet doses of 400 to 500 mg are not necessarily fatal. In rats, the oral LD50 of dextroamphetamine sulfate is 96.8 mg/kg. Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rhabdomyolysis, rapid respiration, hyperpyrexia, confusion, assaultiveness, hallucinations, panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. TREATMENT Consult with a Certified Poison Control Center for up-to-date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic, and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute, severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine (Bedford Laboratories) has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication. Since much of the SPANSULE capsule medication is coated for gradual release, therapy directed at reversing the effects of the ingested drug and at supporting the patient should be continued for as long as overdosage symptoms remain. Saline cathartics are useful for hastening the evacuation of pellets that have not already released medication. page 6 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted. Late evening doses should be avoided because of the resulting insomnia. Narcolepsy Usual dose is 5 to 60 mg per day in divided doses, depending on the individual patient response. Narcolepsy seldom occurs in children under 12 years of age; however, when it does, DEXEDRINE may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until an optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until an optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. SPANSULE capsules may be used for once-a-day dosage wherever appropriate. Attention Deficit Disorder with Hyperactivity The SPANSULE capsule formulation is not recommended for pediatric patients younger than 6 years of age. In pediatric patients 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. SPANSULE capsules may be used for once-a-day dosage wherever appropriate. Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. HOW SUPPLIED DEXEDRINE SPANSULE capsules Each capsule, with brown cap and clear body, contains dextroamphetamine sulfate. The 5-mg capsule is imprinted 5 mg and 512 on the brown cap and is imprinted 5 mg and ap on the clear body. The 10-mg capsule is imprinted 10 mg—513—on the brown cap and is imprinted 10 mg—ap—on the clear body. The 15-mg capsule is imprinted 15 mg and 514 on the brown cap and is imprinted 15 mg and ap on the clear body. A narrow bar appears above and below 15 mg and 514. 5 mg 90s: NDC 52054-512-09 10 mg 90s: NDC 52054-513-09 15 mg 90s: NDC 52054-514-09 Store at controlled room temperature between 20° and 25°C (68° and 77°F) [see USP]. Dispense in a tight, light-resistant container. Manufactured by: Catalent Pharma Solutions Winchester, KY 40391 For: Amedra Pharmaceuticals LLC Horsham, PA 19044 LB# 793-06 Rev. May, 2013 For additional copies of the printed patient information/medication guide, please visit www.amedrapharma.com or contact us at 1-888 894-6528. MEDICATION GUIDE DEXEDRINE® (dextroamphetamine sulfate) SPANSULE® sustained release capsules company logo Read the Medication Guide that comes with DEXEDRINE before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with DEXEDRINE. page 7 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What is the most important information I should know about DEXEDRINE? The following have been reported with use of DEXEDRINE and other stimulant medicines. 1. Heart-related problems: • Sudden death in patients who have heart problems or heart defects • Stroke and heart attack in adults • Increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting DEXEDRINE. Your doctor should check your or your child's blood pressure and heart rate regularly during treatment with DEXEDRINE. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking DEXEDRINE. 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking DEXEDRINE, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. 3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: • fi ngers o r t o es m a y feel num b, c ool , pai n f u l • fi ngers o r t o es m a y chan ge c o l o r fr om pal e , t o bl ue, t o red Tell yo u r do ctor if y o u h a v e o r you r ch ild h a s nu m b n e ss, p a in , sk in co lor ch ang e , or sen s itiv ity to te m p er atu r e in your f i ng er s or t o es. Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking DEXEDRINE. What is DEXEDRINE? DEXEDRINE is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). DEXEDRINE may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. DEXEDRINE should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. DEXEDRINE is also used in the treatment of a sleep disorder called narcolepsy. DEXEDRINE is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep DEXEDRINE in a safe place to prevent misuse and abuse. Selling or giving away DEXEDRINE may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take DEXEDRINE? DEXEDRINE should not be taken if you or your child: • Have heart disease or hardening of the arteries • Have moderate to severe high blood pressure • Have hyperthyroidism • Have an eye problem called glaucoma page 8 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Are very anxious, tense, or agitated • Have a history of drug abuse • Are taking or have taken within the past 14 days an antidepression medicine called a monoamine oxidase inhibitor or MAOI. • Is sensitive to, allergic to, or had a reaction to other stimulant medicines DEXEDRINE is not recommended for use in children younger than 6 years old. DEXEDRINE may not be right for you or your child. Before starting DEXEDRINE tell your or your child’s doctor about all health conditions (or a family history of) including: • Heart problems, heart defects, high blood pressure • Mental problems including psychosis, mania, bipolar illness, or depression • Tics or Tourette’s syndrome • Thyroid problems • Seizures or have had an abnormal brain wave test (EEG) • Circu lation problems in fingers and toes Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding. Can DEXEDRINE be taken with other medicines? Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. DEXEDRINE and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking DEXEDRINE. Your doctor will decide whether DEXEDRINE can be taken with other medicines. Especially tell your doctor if you or your child takes: • Anti-depression medicines including MAOIs • Blood pressure medicines • Antacids • Seizure medicines Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking DEXEDRINE without talking to your doctor first. How should DEXEDRINE be taken? • Take DEXEDRINE exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. • DEXEDRINE comes as a capsule. • DEXEDRINE SPANSULE capsules are usually taken once a day in the morning. DEXEDRINE SPANSULE is an extended release capsule. It releases medicine into your body throughout the day. • From time to time, your doctor may stop treatment with DEXEDRINE for a while to check ADHD symptoms. • Your doctor may do regular checks of the blood, heart, and blood pressure while taking DEXEDRINE. Children should have their height and weight checked often while taking DEXEDRINE. Treatment with DEXEDRINE may be stopped if a problem is found during these check-ups. • If you or your child takes too much DEXEDRINE or overdoses, call your doctor or poison control center right away, or get emergency treatment What are possible side effects of DEXEDRINE? See “What is the most important information I should know about DEXEDRINE?” for information on reported heart and mental problems. Other serious side effects include: • Slowing of growth (height and weight) in children page 9 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Seizures, mainly in patients with a history of seizures • Eyesight changes or blurred vision Common side effects include: • Fast heart beat • Decreased appetite • Tremors • Headache • Trouble sleeping • Dizziness • Stomach upset • Weight loss • Dry mouth DEXEDRINE may affect your or your child’s ability to drive or do other dangerous activities. Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DEXEDRINE? • Store DEXEDRINE SPANSULE capsules in a safe place at room temperature, 68° to 77°F (20° to 25°C). Protect from light. • Keep DEXEDRINE and all medicines out of the reach of children. General information about DEXEDRINE Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DEXEDRINE for a condition for which it was not prescribed. Do not give DEXEDRINE to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about DEXEDRINE. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about DEXEDRINE that was written for healthcare professionals. For more information about DEXEDRINE, please contact Amedra Pharmaceuticals at 1-888-894-6528 or visit www.amedrapharma.com. What are the ingredients in DEXEDRINE? Active Ingredient: Dextroamphetamine sulfate Inactive Ingredients: SPANSULE Capsules: Cetyl alcohol, D&C Yellow No. 10, dibutyl sebacate, ethylcellulose, FD&C Blue No. 1, FD&C Blue No. 1 aluminum lake, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, hypromellose, polyethylene glycol, povidone, sodium lauryl sulfate, sugar spheres and trace amounts of other inactive ingredients. This Medication Guide has been approved by the U.S. Food and Drug Administration. July 2008 DXD:3MG. Manufactured by Catalent Pharma Solutions Winchester, KY 40391 For Amedra Pharmaceuticals LLC Horsham, PA 19044 LB# 797-06 Rev. May, 2013 For additional copies of the printed patient information/medication guide, please visit www.amedrapharma.com or contact us at 1-888-894-6528. page 10 of 12 Reference ID: 3322879 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:07.707761	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017078s046lbl.pdf', 'application_number': 17078, 'submission_type': 'SUPPL ', 'submission_number': 46}
10,960	DEXEDRINE® (dextroamphetamine sulfate) SPANSULE® sustained release capsules Cll Rx Only WARNING: AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINES MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS. DESCRIPTION: DEXEDRINE (dextroamphetamine sulfate) is the dextro isomer of the compound d,1-amphetamine sulfate, a sympathomimetic amine of the amphetamine group. Chemically, dextroamphetamine is d-alpha-methylphenethylamine, and is present in all forms of DEXEDRINE as the neutral sulfate. Structural formula: structural formula SPANSULE capsules: Each SPANSULE sustained-release capsule is so prepared that an initial dose is released promptly and the remaining medication is released gradually over a prolonged period. Each capsule, with brown cap and clear body, contains dextroamphetamine sulfate. The 5-mg capsule is imprinted 5 mg and 512 on the brown cap and is imprinted 5 mg and ap on the clear body. The 10-mg capsule is imprinted 10 mg—513—on the brown cap and is imprinted 10 mg—ap—on the clear body. The 15-mg capsule is imprinted 15 mg and 514 on the brown cap and is imprinted 15 mg and ap on the clear body. A narrow bar appears above and below 15 mg and 514. Product reformulation in 1996 has caused a minor change in the color of the time-released pellets within each capsule. Inactive ingredients now consist of cetyl alcohol, D&C Yellow No. 10, dibutyl sebacate, ethylcellulose, FD&C Blue No. 1, FD&C Blue No. 1 aluminum lake, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, hypromellose, polyethylene glycol, povidone, sodium lauryl sulfate, sugar spheres, and trace amounts of other inactive ingredients. CLINICAL PHARMACOLOGY: Amphetamines are noncatecholamine, sympathomimetic amines with CNS stimulant activity. Peripheral actions include elevations of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant action. There is neither specific evidence that clearly establishes the mechanism whereby amphetamines produce mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. DEXEDRINE SPANSULE Capsules are formulated to release the active drug substance in vivo in a more gradual fashion than the standard formulation, as demonstrated by blood levels. The formulation has not been shown superior in effectiveness over the same dosage of the standard, noncontrolled-release formulations given in divided doses. Pharmacokinetics: The pharmacokinetics of the tablet and sustained-release capsule were compared in 12 healthy subjects. The extent of bioavailability of the sustained-release capsule was similar compared to the immediate-release tablet. Following administration of three 5-mg tablets, average maximal dextroamphetamine plasma concentrations (Cmax) of 36.6 ng/mL were achieved at approximately 3 hours. Following administration of one 15-mg sustained-release capsule, maximal dextroamphetamine plasma concentrations were obtained approximately 8 hours after dosing. The average Cmax was 23.5 ng/mL. The average plasma T½ was similar for both the tablet and sustained-release capsule and was approximately 12 hours. In 12 healthy subjects, the rate and extent of dextroamphetamine absorption were similar following administration of the sustained-release capsule formulation in the fed (58 to 75 gm fat) and fasted state. INDICATIONS AND USAGE: DEXEDRINE is indicated in: Narcolepsy Attention Deficit Disorder with Hyperactivity As an integral part of a total treatment program that typically includes other measures (psychological, educational, social) for patients page 1 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (ages 6 years to 16 years) with this syndrome. A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of the hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go”; excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presences of the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program DEXEDRINE is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Stimulants are not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms. CONTRAINDICATIONS Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated states. Patients with a history of drug abuse. During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death in Patients With Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS). Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS). Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms page 2 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of, or worsening of, aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non- medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non- medication treated children older than 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Peripheral Vasculopathy, including Raynaud’s phenomenon Stimulants, including DEXEDRINE, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. PRECAUTIONS General The least amount feasible should be prescribed or dispensed at 1 time in order to minimize the possibility of overdosage. Information for Patients: Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. page 3 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with dextroamphetamine and should counsel them in its appropriate use. A patient Medication Guide is available for DEXEDRINE. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon] • Instruct patients beginning treatment with DEXEDRINE about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. • Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. • Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking DEXEDRINE. • Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Drug Interactions Acidifying Agents Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines. Urinary acidifying agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines. Adrenergic Blockers Adrenergic blockers are inhibited by amphetamines. Alkalinizing Agents Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines. Antidepressants, Tricyclic Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. MAO Inhibitors MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results. Antihistamines Amphetamines may counteract the sedative effect of antihistamines. Antihypertensives Amphetamines may antagonize the hypotensive effects of antihypertensives. Chlorpromazine Chlorpromazine blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning. Ethosuximide Amphetamines may delay intestinal absorption of ethosuximide. Haloperidol Haloperidol blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines. Lithium Carbonate The stimulatory effects of amphetamines may be inhibited by lithium carbonate. page 4 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Meperidine Amphetamines potentiate the analgesic effect of meperidine. Methenamine Therapy Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy. Norepinephrine Amphetamines enhance the adrenergic effect of norepinephrine. Phenobarbital Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur. Veratrum Alkaloids Amphetamines inhibit the hypotensive effect of veratrum alkaloids. Drug/Laboratory Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations. Carcinogenesis/Mutagenesis Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of DEXEDRINE have not been performed. Pregnancy Teratogenic Effects Pregnancy Category C. DEXEDRINE has been shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses approximately 41 times the maximum human dose. Embryotoxic effects were not seen in New Zealand white rabbits given the drug in doses 7 times the human dose nor in rats given 12.5 times the maximum human dose. While there are no adequate and well-controlled studies in pregnant women, there has been 1 report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. DEXEDRINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude. Nursing Mothers Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing. Pediatric Use Long-term effects of amphetamines in pediatric patients have not been well established. DEXEDRINE is not recommended for use in pediatric patients younger than 6 years of age with Attention Deficit Disorder with Hyperactivity described under INDICATIONS AND USAGE. Clinical experience suggests that in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder. Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications. Data are inadequate to determine whether chronic administration of amphetamines may be associated with growth inhibition; therefore, growth should be monitored during treatment. Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe amphetamines should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his or her age. Prescription should not depend page 5 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with amphetamines is usually not indicated. ADVERSE REACTIONS Cardiovascular Palpitations, tachycardia, elevation of blood pressure. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System Psychotic episodes at recommended doses (rare), overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonic tics, and Tourette’s syndrome. Gastrointestinal Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic Urticaria. Endocrine Impotence, changes in libido, frequent or prolonged erections. Musculoskeletal Rhabdomyolysis. DRUG ABUSE AND DEPENDENCE Dextroamphetamine sulfate is a Schedule II controlled substance. Amphetamines have been extensively abused. Tolerance, extreme psychological dependence and severe social disability have occurred. There are reports of patients who have increased the dosage to many times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. This is rare with oral amphetamines. OVERDOSAGE Individual patient response to amphetamines varies widely. While toxic symptoms occasionally occur as an idiosyncrasy at doses as low as 2 mg, they are rare with doses of less than 15 mg; 30 mg can produce severe reactions, yet doses of 400 to 500 mg are not necessarily fatal. In rats, the oral LD50 of dextroamphetamine sulfate is 96.8 mg/kg. Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rhabdomyolysis, rapid respiration, hyperpyrexia, confusion, assaultiveness, hallucinations, panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. TREATMENT Consult with a Certified Poison Control Center for up-to-date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic, and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute, severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine (Bedford Laboratories) has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication. Since much of the SPANSULE capsule medication is coated for gradual release, therapy directed at reversing the effects of the ingested drug and at supporting the patient should be continued for as long as overdosage symptoms remain. Saline cathartics are useful for hastening the evacuation of pellets that have not already released medication. DOSAGE AND ADMINISTRATION Amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted. Late evening doses should be avoided because of the resulting insomnia. Narcolepsy page 6 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usual dose is 5 to 60 mg per day in divided doses, depending on the individual patient response. Narcolepsy seldom occurs in children under 12 years of age; however, when it does, DEXEDRINE may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until an optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until an optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. SPANSULE capsules may be used for once-a-day dosage wherever appropriate. Attention Deficit Disorder with Hyperactivity The SPANSULE capsule formulation is not recommended for pediatric patients younger than 6 years of age. In pediatric patients 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. SPANSULE capsules may be used for once-a-day dosage wherever appropriate. Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. HOW SUPPLIED DEXEDRINE SPANSULE capsules Each capsule, with brown cap and clear body, contains dextroamphetamine sulfate. The 5-mg capsule is imprinted 5 mg and 512 on the brown cap and is imprinted 5 mg and ap on the clear body. The 10-mg capsule is imprinted 10 mg—513—on the brown cap and is imprinted 10 mg—ap—on the clear body. The 15-mg capsule is imprinted 15 mg and 514 on the brown cap and is imprinted 15 mg and ap on the clear body. A narrow bar appears above and below 15 mg and 514. 5 mg 90s: NDC 52054-512-09 10 mg 90s: NDC 52054-513-09 15 mg 90s: NDC 52054-514-09 Store at controlled room temperature between 20° and 25°C (68° and 77°F) [see USP]. Dispense in a tight, light-resistant container. Manufactured by: Catalent Pharma Solutions Winchester, KY 40391 For: Amedra Pharmaceuticals LLC Horsham, PA 19044 LB# 793-08 Rev. February, 2015 For additional copies of the printed patient information/medication guide, please visit www.amedrapharma.com or contact us at 1-888 894-6528. page 7 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE DEXEDRINE® (dextroamphetamine sulfate) SPANSULE® sustained release capsules company logo Read the Medication Guide that comes with DEXEDRINE before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with DEXEDRINE. What is the most important information I should know about DEXEDRINE? The following have been reported with use of DEXEDRINE and other stimulant medicines. 1. Heart-related problems: • Sudden death in patients who have heart problems or heart defects • Stroke and heart attack in adults • Increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting DEXEDRINE. Your doctor should check your or your child's blood pressure and heart rate regularly during treatment with DEXEDRINE. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking DEXEDRINE. 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking DEXEDRINE, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. 3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: • fingers or toes may feel numb, cool, painful • fingers or toes may change color from pale, to blue, to red Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes. Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking DEXEDRINE. What is DEXEDRINE? DEXEDRINE is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). DEXEDRINE may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. DEXEDRINE should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. DEXEDRINE is also used in the treatment of a sleep disorder called narcolepsy. DEXEDRINE is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep DEXEDRINE in a safe place to prevent misuse and abuse. Selling or giving away DEXEDRINE may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take DEXEDRINE? page 8 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DEXEDRINE should not be taken if you or your child: • Have heart disease or hardening of the arteries • Have moderate to severe high blood pressure • Have hyperthyroidism • Have an eye problem called glaucoma • Are very anxious, tense, or agitated • Have a history of drug abuse • Are taking or have taken within the past 14 days an antidepression medicine called a monoamine oxidase inhibitor or MAOI. • Is sensitive to, allergic to, or had a reaction to other stimulant medicines DEXEDRINE is not recommended for use in children younger than 6 years old. DEXEDRINE may not be right for you or your child. Before starting DEXEDRINE tell your or your child’s doctor about all health conditions (or a family history of) including: • Heart problems, heart defects, high blood pressure • Mental problems including psychosis, mania, bipolar illness, or depression • Tics or Tourette’s syndrome • Thyroid problems • Seizures or have had an abnormal brain wave test (EEG) • Circulation problems in fingers and toes Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding. Can DEXEDRINE be taken with other medicines? Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. DEXEDRINE and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking DEXEDRINE. Your doctor will decide whether DEXEDRINE can be taken with other medicines. Especially tell your doctor if you or your child takes: • Anti-depression medicines including MAOIs • Blood pressure medicines • Antacids • Seizure medicines Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking DEXEDRINE without talking to your doctor first. How should DEXEDRINE be taken? • Take DEXEDRINE exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. • DEXEDRINE comes as a capsule. • DEXEDRINE SPANSULE capsules are usually taken once a day in the morning. DEXEDRINE SPANSULE is an extended release capsule. It releases medicine into your body throughout the day. • From time to time, your doctor may stop treatment with DEXEDRINE for a while to check ADHD symptoms. • Your doctor may do regular checks of the blood, heart, and blood pressure while taking DEXEDRINE. Children should have their height and weight checked often while taking DEXEDRINE. Treatment with DEXEDRINE may be stopped if a problem is found during these check-ups. • If you or your child takes too much DEXEDRINE or overdoses, call your doctor or poison control center right away, or get emergency treatment page 9 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What are possible side effects of DEXEDRINE? See “What is the most important information I should know about DEXEDRINE?” for information on reported heart and mental problems. Other serious side effects include: • Slowing of growth (height and weight) in children • Seizures, mainly in patients with a history of seizures • Eyesight changes or blurred vision Common side effects include: • Fast heart beat • Decreased appetite • Tremors • Headache • Trouble sleeping • Dizziness • Stomach upset • Weight loss • Dry mouth DEXEDRINE may affect your or your child’s ability to drive or do other dangerous activities. Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DEXEDRINE? • Store DEXEDRINE SPANSULE capsules in a safe place at room temperature, 68° to 77°F (20° to 25°C). Protect from light. • Keep DEXEDRINE and all medicines out of the reach of children. General information about DEXEDRINE Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DEXEDRINE for a condition for which it was not prescribed. Do not give DEXEDRINE to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about DEXEDRINE. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about DEXEDRINE that was written for healthcare professionals. For more information about DEXEDRINE, please contact Amedra Pharmaceuticals at 1-888-894-6528 or visit www.amedrapharma.com. What are the ingredients in DEXEDRINE? Active Ingredient: Dextroamphetamine sulfate Inactive Ingredients: SPANSULE Capsules: Cetyl alcohol, D&C Yellow No. 10, dibutyl sebacate, ethylcellulose, FD&C Blue No. 1, FD&C Blue No. 1 aluminum lake, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, hypromellose, polyethylene glycol, povidone, sodium lauryl sulfate, sugar spheres and trace amounts of other inactive ingredients. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by Catalent Pharma Solutions Winchester, KY 40391 For Amedra Pharmaceuticals LLC Horsham, PA 19044 LB# 797-07 Rev. October, 2013 page 10 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For additional copies of the printed patient information/medication guide, please visit www.amedrapharma.com or contact us at 1-888-894-6528. page 11 of 11 Reference ID: 3734637 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:07.974202	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017078s048lbl.pdf', 'application_number': 17078, 'submission_type': 'SUPPL ', 'submission_number': 48}
10,961	NDA 17-084/S-017 Page 3 Product info This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-084/S-017 Page 4 Phosphocol® P 32 Chromic Phosphate P 32 Suspension Rx Only. Therapeutic – intraperitoneal or intracavitary injection only for treatment of peritoneal or pleural effusions caused by metastatic disease. DESCRIPTION Phosphocol® P 32 is supplied as a sterile, nonpyrogenic aqueous suspension in a 30% dextrose solution with 2% benzyl alcohol added as preservative. Each milliliter contains 1 mg sodium acetate. Sodium hydroxide or hydrochloric acid may be present for pH adjustment. ACTIONS Local irradiation by beta emission. INDICATIONS Phosphocol P 32 is employed by intracavitary instillation for the treatment of peritoneal or pleural effusions caused by metastatic disease, and may be injected interstitially for the treatment of cancer. CONTRAINDICATIONS Chromic phosphate P 32 therapy should not be used in the presence of ulcerative tumors. Administration should not be made in exposed cavities or where there is evidence of loculation unless the extent of loculation is determined. WARNINGS Not for intravascular use. This radiopharmaceutical should not be administered to patients who are pregnant or during lactation unless the therapeutic benefits outweigh the potential hazards. Radiopharmaceuticals should be used only by physicians who are qualified by specific training in the safe use and handling of radionuclides produced by nuclear reactor or particle accelerator and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides. Leukemia Phosphocol P 32 may increase the risk for leukemia in certain situations. Two children (ages 9 and 14) with hemophilia developed acute lymphocytic leukemia approximately 10 months after intra-articular injections of Phosphocol P 32 (0.6 and 1.5 mCi total dose). Phosphocol P 32 is not indicated in the intra-articular treatment of hemarthroses. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-084/S-017 Page 5 PRECAUTIONS General As in the use of any other radioactive material care should be taken to insure minimum radiation exposure to the patient, consistent with proper patient management, and to insure minimum radiation exposure to occupational workers. Careful intracavitary instillation is required to avoid placing the dose of chromic phosphate P 32 into intrapleural or intraperitoneal loculations, bowel lumen or into the body wall. Intestinal fibrosis or necrosis and chronic fibrosis of the body wall have been reported to result from unrecognized misplacement of the therapeutic agent. The presence of large tumor masses indicates the need for other forms of treatment. However, when other forms of treatment fail to control the effusion, chromic phosphate P 32 may be useful. In bloody effusion, treatment may be less effective. Pediatric Use Safety and effectiveness in pediatric patients has not been established. Risk of Malignancy Acute lymphocytic leukemia has been reported in children following the intra-articular administration of Phosphocol P 32 (see WARNINGS). ADVERSE REACTIONS Untoward effects may be associated with use of chromic phosphate P 32. These include transitory radiation sickness, bone marrow depression, pleuritis, peritonitis, nausea and abdominal cramping. Radiation damage may occur if accidentally injected interstitially or into a loculation. Post-marketing Experience The following adverse reactions associated with the use of Phosphocol P 32 have been identified during post approval use: Leukemia in Children (see WARNINGS) Radiation injury (necrosis and fibrosis) to the small bowel, cecum, and bladder following administration of P 32 into the peritoneal cavity. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-084/S-017 Page 6 DOSAGE AND ADMINISTRATION The suggested dose range employed in the average patient (70 kg) is: Intraperitoneal instillation: 370 to 740 megabecquerels (10 to 20 millicuries) Intrapleural instillation: 222 to 444 megabecquerels (6 to 12 millicuries) Doses for interstitial use should be based on estimated gram weight of tumor, about 3.7 to 18.5 MBq/gm (0.1 to 0.5 mCi/gm). The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. PHYSICAL CHARACTERISTICS Phosphorus P 32 decays by beta emission with a physical half-life of 14.3 days.1 The mean energy of the beta particle is 695 keV. Table 1. Principal Radiation Emission Data Radiation Mean Percent/ Disintegration Mean Energy (keV) Beta-1 100.0 694.9 The range of the phosphorus P 32 beta particle, which has a maximum energy of 1.71 MeV, is 2.9 mm of aluminum. To correct for physical decay of this radionuclide, the percentages that remain at selected time intervals before and after the day of calibration are shown in Table 2. Stabin MG, da Luz CQPL. New Decay Data for Internal and External Dose Assessment, Health Phys. 83(4):471-475, 2002. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-084/S-017 Page 7 Table 2. Physical Decay Chart; Phosphorus P 32, Half-life 14.3 days Days Fraction Remaining Days Fraction Remaining Days Fraction Remaining -15 -10 -5 -2 -1 0* 1 2.07 1.62 1.27 1.10 1.05 1.00 0.953 2 5 10 15 20 25 30 0.908 0.785 0.616 0.483 0.379 0.298 0.234 35 40 45 50 55 60 65 0.183 0.144 0.113 0.089 0.070 0.055 0.043 *Calibration Day RADIATION DOSIMETRY The effective half-life of phosphorus P 32 is considered to be equal to its physical half-life, with a residence time of 495 hours. The radiation dose from a uniformly distributed concentration of 37 kilobecquerels (1 microcurie) per gram within a 16-gram prostate is estimated to be equivalent to about 7.3 grays (730 rads)2. Table 3 shows the estimated radiation doses to the prostate and the pleural or peritoneal surfaces3 of an average patient (70 kg) from a dose of 740 megabecquerels (20 millicuries) of phosphorus P 32. In comparison to the distribution in the prostate, the distribution of phosphorus P 32 on the pleural and peritoneal surfaces is non-uniform, with great extremes in local doses. To obtain an estimate of the average dose, the surface area of the pleural and peritoneal cavities can be assumed to amount to 4,000 and 5,000 cm2, respectively. The estimated radiation doses to an average patient (70 kg) with 90% retention of a dose of 740 megabecquerels (20 millicuries) of phosphorus P 32 distributed uniformly over these areas are shown in Table 3. The decreases of the averaged radiation doses at various tissue depths away from the surfaces of the pleural and peritoneal cavities are also tabulated. Stabin MG. A Model of the Prostate Gland for Use in Internal Dosimetry. J Nucl Med 35(3):516-520, 1994. 3 Watson EE, Stabin MG, Davis JL and Eckerman KF. A Model of the Peritoneal Cavity for Use in Internal Dosimetry. J Nucl Med 30:2002-2011, 1989. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-084/S-017 Page 8 Table 3. Estimated Radiation Doses Surface/Organ Pleural Peritoneal Prostate % Retention Area/wt 90 4000 cm2 90 5000 cm2 100 16 gm Depth in tissue (cm) Dose Rate Tissue Dose / 740 MBq (20 mCi) mGy-cm2 MBq-s rad-cm2 µCi-h grays rads grays rads grays rads 0.006 0.018 0.03 0.12 0.21 0.3 0.4 0.75 10 0.53 7 0.42 5.6 0.15 2 0.064 0.85 0.023 0.31 0.0047 0.062 178 17800 125 12500 100 10000 36 3570 15 1520 5.5 550 1 110 134 13400 94 9360 74.9 7490 26.7 2670 11.4 1140 4.1 410 0.83 83 9180 918000 HOW SUPPLIED Catalog Number 470 Phosphocol P 32 - Chromic Phosphate P 32 Suspension (NDC No. 0019-N470-P0) is available in 10 milliliter vials containing 555 megabecquerels (15 millicuries) with a concentration of 185 megabecquerels (5 millicuries) per milliter. The radiopharmaceutical is manufactured with a specific activity of 122 megabecquerels (3.3 millicuries) per milligram Chromic Phosphate at the time of standardization. The U.S. Nuclear Regulatory Commission has approved distribution of this radiopharmaceutical to persons licensed to use byproduct material listed in Section 35.300, and to persons who hold an equivalent license issued by an Agreement State. STORAGE AND HANDLING Store at controlled room temperature 20 to 25°C (68 to 77°F). Revised 020308 Mallinckrodt Inc. Hazelwood, MO 63042 U.S.A. A470I0 Company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:08.000542	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017084s017lbl.pdf', 'application_number': 17084, 'submission_type': 'SUPPL ', 'submission_number': 17}
10,959	structural formula DEXEDRINE® (dextroamphetamine sulfate) SPANSULE® sustained release capsules Cll Rx Only WARNING: AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY. MISUSE OF AMPHETAMINES MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS. DESCRIPTION: DEXEDRINE (dextroamphetamine sulfate) is the dextro isomer of the compound d,1-amphetamine sulfate, a sympathomimetic amine of the amphetamine group. Chemically, dextroamphetamine is d-alpha-methylphenethylamine, and is present in all forms of DEXEDRINE as the neutral sulfate. Structural formula: SPANSULE capsules: Each SPANSULE sustained-release capsule is so prepared that an initial dose is released promptly and the remaining medication is released gradually over a prolonged period. Each capsule, with brown cap and clear body, contains dextroamphetamine sulfate. The 5-mg capsule is imprinted 5 mg and 512 on the brown cap and is imprinted 5 mg and ap on the clear body. The 10-mg capsule is imprinted 10 mg—513—on the brown cap and is imprinted 10 mg—ap—on the clear body. The 15-mg capsule is imprinted 15 mg and 514 on the brown cap and is imprinted 15 mg and ap on the clear body. A narrow bar appears above and below 15 mg and 514. Product reformulation in 1996 has caused a minor change in the color of the time-released pellets within each capsule. Inactive ingredients now consist of cetyl alcohol, D&C Yellow No. 10, dibutyl sebacate, ethylcellulose, FD&C Blue No. 1, FD&C Blue No. 1 aluminum lake, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, hypromellose, polyethylene glycol, povidone, sodium lauryl sulfate, sugar spheres, and trace amounts of other inactive ingredients. CLINICAL PHARMACOLOGY: Amphetamines are noncatecholamine, sympathomimetic amines with CNS stimulant activity. Peripheral actions include elevations of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant action. There is neither specific evidence that clearly establishes the mechanism whereby amphetamines produce mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. DEXEDRINE SPANSULE Capsules are formulated to release the active drug substance in vivo in a more gradual fashion than the standard formulation, as demonstrated by blood levels. The formulation has not been shown superior in effectiveness over the same dosage of the standard, noncontrolled-release formulations given in divided doses. Pharmacokinetics: The pharmacokinetics of the tablet and sustained-release capsule were compared in 12 healthy subjects. The extent of bioavailability of the sustained-release capsule was similar compared to the immediate-release tablet. Following administration of three 5-mg tablets, average maximal dextroamphetamine plasma concentrations (Cmax) of 36.6 ng/mL were achieved at approximately 3 hours. Following administration of one 15-mg sustained-release capsule, maximal dextroamphetamine plasma concentrations were obtained approximately 8 hours after dosing. The average Cmax was 23.5 ng/mL. The average plasma T½ was similar for both the tablet and sustained-release capsule and was approximately 12 hours. In 12 healthy subjects, the rate and extent of dextroamphetamine absorption were similar following administration of the sustained-release capsule formulation in the fed (58 to 75 gm fat) and fasted state. INDICATIONS AND USAGE: DEXEDRINE is indicated in: Narcolepsy Attention Deficit Disorder with Hyperactivity As an integral part of a total treatment program that typically includes other measures (psychological, educational, social) for patients page 1 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (ages 6 years to 16 years) with this syndrome. A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of the hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go”; excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presences of the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program DEXEDRINE is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Stimulants are not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms. CONTRAINDICATIONS Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated states. Patients with a history of drug abuse. During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result). WARNINGS Serious Cardiovascular Events Sudden Death in Patients With Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS). Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS). Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms page 2 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of, or worsening of, aggressive behavior or hostility. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non- medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non- medication treated children older than 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Peripheral Vasculopathy, including Raynaud’s phenomenon Stimulants, including DEXEDRINE, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. PRECAUTIONS General The least amount feasible should be prescribed or dispensed at 1 time in order to minimize the possibility of overdosage. Information for Patients: Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. page 3 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with dextroamphetamine and should counsel them in its appropriate use. A patient Medication Guide is available for DEXEDRINE. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon] • Instruct patients beginning treatment with DEXEDRINE about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. • Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. • Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking DEXEDRINE. • Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Drug Interactions Acidifying Agents Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines. Urinary acidifying agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines. Adrenergic Blockers Adrenergic blockers are inhibited by amphetamines. Alkalinizing Agents Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines. Antidepressants, Tricyclic Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. MAO Inhibitors MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results. Antihistamines Amphetamines may counteract the sedative effect of antihistamines. Antihypertensives Amphetamines may antagonize the hypotensive effects of antihypertensives. Chlorpromazine Chlorpromazine blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning. Ethosuximide Amphetamines may delay intestinal absorption of ethosuximide. Haloperidol Haloperidol blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines. Lithium Carbonate The stimulatory effects of amphetamines may be inhibited by lithium carbonate. page 4 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Meperidine Amphetamines potentiate the analgesic effect of meperidine. Methenamine Therapy Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy. Norepinephrine Amphetamines enhance the adrenergic effect of norepinephrine. Phenobarbital Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur. Veratrum Alkaloids Amphetamines inhibit the hypotensive effect of veratrum alkaloids. Drug/Laboratory Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations. Carcinogenesis/Mutagenesis Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of DEXEDRINE have not been performed. Pregnancy Teratogenic Effects Pregnancy Category C. DEXEDRINE has been shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses approximately 41 times the maximum human dose. Embryotoxic effects were not seen in New Zealand white rabbits given the drug in doses 7 times the human dose nor in rats given 12.5 times the maximum human dose. While there are no adequate and well-controlled studies in pregnant women, there has been 1 report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. DEXEDRINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude. Nursing Mothers Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing. Pediatric Use Long-term effects of amphetamines in pediatric patients have not been well established. DEXEDRINE is not recommended for use in pediatric patients younger than 6 years of age with Attention Deficit Disorder with Hyperactivity described under INDICATIONS AND USAGE. Clinical experience suggests that in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder. Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications. Data are inadequate to determine whether chronic administration of amphetamines may be associated with growth inhibition; therefore, growth should be monitored during treatment. Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe amphetamines should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his or her age. Prescription should not depend page 5 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with amphetamines is usually not indicated. ADVERSE REACTIONS Cardiovascular Palpitations, tachycardia, elevation of blood pressure. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System Psychotic episodes at recommended doses (rare), overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonic tics, and Tourette’s syndrome. Gastrointestinal Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic Urticaria. Endocrine Impotence, changes in libido, frequent or prolonged erections. DRUG ABUSE AND DEPENDENCE Dextroamphetamine sulfate is a Schedule II controlled substance. Amphetamines have been extensively abused. Tolerance, extreme psychological dependence and severe social disability have occurred. There are reports of patients who have increased the dosage to many times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. This is rare with oral amphetamines. OVERDOSAGE Individual patient response to amphetamines varies widely. While toxic symptoms occasionally occur as an idiosyncrasy at doses as low as 2 mg, they are rare with doses of less than 15 mg; 30 mg can produce severe reactions, yet doses of 400 to 500 mg are not necessarily fatal. In rats, the oral LD50 of dextroamphetamine sulfate is 96.8 mg/kg. Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rhabdomyolysis, rapid respiration, hyperpyrexia, confusion, assaultiveness, hallucinations, panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. TREATMENT Consult with a Certified Poison Control Center for up-to-date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic, and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute, severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine (Bedford Laboratories) has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication. Since much of the SPANSULE capsule medication is coated for gradual release, therapy directed at reversing the effects of the ingested drug and at supporting the patient should be continued for as long as overdosage symptoms remain. Saline cathartics are useful for hastening the evacuation of pellets that have not already released medication. DOSAGE AND ADMINISTRATION Amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted. Late evening doses should be avoided because of the resulting insomnia. Narcolepsy Usual dose is 5 to 60 mg per day in divided doses, depending on the individual patient response. Narcolepsy seldom occurs in children under 12 years of age; however, when it does, DEXEDRINE may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until an optimal page 6 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until an optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. SPANSULE capsules may be used for once-a-day dosage wherever appropriate. Attention Deficit Disorder with Hyperactivity The SPANSULE capsule formulation is not recommended for pediatric patients younger than 6 years of age. In pediatric patients 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. SPANSULE capsules may be used for once-a-day dosage wherever appropriate. Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. HOW SUPPLIED DEXEDRINE SPANSULE capsules Each capsule, with brown cap and clear body, contains dextroamphetamine sulfate. The 5-mg capsule is imprinted 5 mg and 512 on the brown cap and is imprinted 5 mg and ap on the clear body. The 10-mg capsule is imprinted 10 mg—513—on the brown cap and is imprinted 10 mg—ap—on the clear body. The 15-mg capsule is imprinted 15 mg and 514 on the brown cap and is imprinted 15 mg and ap on the clear body. A narrow bar appears above and below 15 mg and 514. 5 mg 90s: NDC 52054-512-09 10 mg 90s: NDC 52054-513-09 15 mg 90s: NDC 52054-514-09 Store at controlled room temperature between 20° and 25°C (68° and 77°F) [see USP]. Dispense in a tight, light-resistant container. Manufactured by: Catalent Pharma Solutions Winchester, KY 40391 For: Amedra Pharmaceuticals LLC Horsham, PA 19044 LB# 793-07 Rev. October, 2013 For additional copies of the printed patient information/medication guide, please visit www.amedrapharma.com or contact us at 1-888 894-6528. page 7 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE DEXEDRINE® (dextroamphetamine sulfate) SPANSULE® sustained release capsules Read the Medication Guide that comes with DEXEDRINE before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with DEXEDRINE. What is the most important information I should know about DEXEDRINE? The following have been reported with use of DEXEDRINE and other stimulant medicines. 1. Heart-related problems: • Sudden death in patients who have heart problems or heart defects • Stroke and heart attack in adults • Increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting DEXEDRINE. Your doctor should check your or your child's blood pressure and heart rate regularly during treatment with DEXEDRINE. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking DEXEDRINE. 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking DEXEDRINE, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. 3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: • fingers or toes may feel numb, cool, painful • fingers or toes may change color from pale, to blue, to red Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes. Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking DEXEDRINE. What is DEXEDRINE? DEXEDRINE is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). DEXEDRINE may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. DEXEDRINE should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. DEXEDRINE is also used in the treatment of a sleep disorder called narcolepsy. DEXEDRINE is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep DEXEDRINE in a safe place to prevent misuse and abuse. Selling or giving away DEXEDRINE may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. page 8 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Who should not take DEXEDRINE? DEXEDRINE should not be taken if you or your child: • Have heart disease or hardening of the arteries • Have moderate to severe high blood pressure • Have hyperthyroidism • Have an eye problem called glaucoma • Are very anxious, tense, or agitated • Have a history of drug abuse • Are taking or have taken within the past 14 days an antidepression medicine called a monoamine oxidase inhibitor or MAOI. • Is sensitive to, allergic to, or had a reaction to other stimulant medicines DEXEDRINE is not recommended for use in children younger than 6 years old. DEXEDRINE may not be right for you or your child. Before starting DEXEDRINE tell your or your child’s doctor about all health conditions (or a family history of) including: • Heart problems, heart defects, high blood pressure • Mental problems including psychosis, mania, bipolar illness, or depression • Tics or Tourette’s syndrome • Thyroid problems • Seizures or have had an abnormal brain wave test (EEG) • Circulation problems in fingers and toes Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding. Can DEXEDRINE be taken with other medicines? Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. DEXEDRINE and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking DEXEDRINE. Your doctor will decide whether DEXEDRINE can be taken with other medicines. Especially tell your doctor if you or your child takes: • Anti-depression medicines including MAOIs • Blood pressure medicines • Antacids • Seizure medicines Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking DEXEDRINE without talking to your doctor first. How should DEXEDRINE be taken? • Take DEXEDRINE exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. • DEXEDRINE comes as a capsule. • DEXEDRINE SPANSULE capsules are usually taken once a day in the morning. DEXEDRINE SPANSULE is an extended release capsule. It releases medicine into your body throughout the day. • From time to time, your doctor may stop treatment with DEXEDRINE for a while to check ADHD symptoms. • Your doctor may do regular checks of the blood, heart, and blood pressure while taking DEXEDRINE. Children should have their height and weight checked often while taking DEXEDRINE. Treatment with DEXEDRINE may be stopped if a problem is found during these check-ups. page 9 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • If you or your child takes too much DEXEDRINE or overdoses, call your doctor or poison control center right away, or get emergency treatment What are possible side effects of DEXEDRINE? See “What is the most important information I should know about DEXEDRINE?” for information on reported heart and mental problems. Other serious side effects include: • Slowing of growth (height and weight) in children • Seizures, mainly in patients with a history of seizures • Eyesight changes or blurred vision Common side effects include: • Fast heart beat • Decreased appetite • Tremors • Headache • Trouble sleeping • Dizziness • Stomach upset • Weight loss • Dry mouth DEXEDRINE may affect your or your child’s ability to drive or do other dangerous activities. Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DEXEDRINE? • Store DEXEDRINE SPANSULE capsules in a safe place at room temperature, 68° to 77°F (20° to 25°C). Protect from light. • Keep DEXEDRINE and all medicines out of the reach of children. General information about DEXEDRINE Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DEXEDRINE for a condition for which it was not prescribed. Do not give DEXEDRINE to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about DEXEDRINE. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about DEXEDRINE that was written for healthcare professionals. For more information about DEXEDRINE, please contact Amedra Pharmaceuticals at 1-888-894-6528 or visit www.amedrapharma.com. What are the ingredients in DEXEDRINE? Active Ingredient: Dextroamphetamine sulfate Inactive Ingredients: SPANSULE Capsules: Cetyl alcohol, D&C Yellow No. 10, dibutyl sebacate, ethylcellulose, FD&C Blue No. 1, FD&C Blue No. 1 aluminum lake, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, hypromellose, polyethylene glycol, povidone, sodium lauryl sulfate, sugar spheres and trace amounts of other inactive ingredients. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by Catalent Pharma Solutions Winchester, KY 40391 For Amedra Pharmaceuticals LLC page 10 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Horsham, PA 19044 LB# 797-07 Rev. October, 2013 For additional copies of the printed patient information/medication guide, please visit www.amedrapharma.com or contact us at 1-888-894-6528. page 11 of 17 Reference ID: 3418238 This label may not be the latest approved by FDA. 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10,962	NDA 17-087/S-047 Page 3 ĒTHRANE (enflurane, USP) Liquid For Inhalation Rx only DESCRIPTION ĒTHRANE (enflurane, USP), a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether (CHF2OCF2CHFCl). The boiling point is 56.5ºC at 760 mm Hg, and the vapor pressure (in mm Hg) is 175 at 20ºC, 218 at 25ºC, and 345 at 36ºC. Vapor pressures can be calculated using the equation: A = 7.967 log10Pvap = A + B/T B = -1678.4 T = ºC + 273.16 (Kelvin) The specific gravity (25º/25ºC) is 1.517. The refractive index at 20ºC is 1.3026-1.3030. The blood/gas coefficient is 1.91 at 37ºC and the oil/gas coefficient is 98.5 at 37ºC. Enflurane is a clear, colorless, stable liquid whose purity exceeds 99.9% (area percent by gas chromatography). No stabilizers are added as these have been found, through controlled laboratory tests, to be unnecessary even in the presence of ultraviolet light. Enflurane is stable to strong base, does not decompose in contact with soda lime (at normal operating temperatures), and does not react with aluminum, tin, brass, iron or copper. The partition coefficients of enflurane at 25ºC are 74 in conductive rubber and 120 in polyvinyl chloride. CLINICAL PHARMACOLOGY ĒTHRANE (enflurane, USP) is an inhalation anesthetic. The MAC (minimum alveolar concentration) in man is 1.68% in pure oxygen, 0.57 in 70% nitrous oxide, 30% oxygen, and 1.17 in 30% nitrous oxide, 70% oxygen. Induction of and recovery from anesthesia with enflurane are rapid. Enflurane has a mild, sweet odor. Enflurane may provide a mild stimulus to salivation or tracheobronchial secretions. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia can be changed rapidly by changing the inspired enflurane concentration. Enflurane reduces ventilation as depth of anesthesia increases. High PaCO2 levels can be obtained at deeper levels of anesthesia if ventilation is not supported. Enflurane provokes a sigh response reminiscent of that seen with diethyl ether. There is a decrease in blood pressure with induction of anesthesia, followed by a return to near normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding increases This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-087/S-047 Page 4 in hypotension. Heart rate remains relatively constant without significant bradycardia. Electrocardiographic monitoring or recordings indicate that cardiac rhythm remains stable. Elevation of the carbon dioxide level in arterial blood does not alter cardiac rhythm. Studies in man indicate a considerable margin of safety in the administration of epinephrine-containing solutions during enflurane anesthesia. Enflurane anesthesia has been used in excision of pheochromocytoma in man without ventricular arrhythmias. On the basis of studies in patients anesthetized with enflurane and injected with epinephrine-containing solutions to achieve hemostasis in a highly vascular area (transsphenoidal surgery), up to 2 micrograms per kilogram (2 µg/kg) of epinephrine may be injected subcutaneously over a 10 minute period in patients judged to have ordinary tolerance to epinephrine administration. This would represent up to 14 mL of 1:100,000 epinephrine-containing solution (10 µg/mL), or the equivalent quantity, in a 70 kilogram patient. This may be repeated up to 3 times per hour (total 42 mL per hour). The concomitant administration of lidocaine enhances the safety of the use of epinephrine during enflurane anesthesia. This effect of lidocaine is dose related. All customary precautions in the use of vasoconstrictor substances should be observed. Muscle relaxation may be adequate for intra-abdominal operations at normal levels of anesthesia. Muscle relaxants may be used to achieve greater relaxation and all commonly used muscle relaxants are compatible with enflurane. THE NON-DEPOLARIZING MUSCLE RELAXANTS ARE POTENTIATED. In the normal 70 kg adult, 6 to 9 mg of d-tubocurarine or 1.0 to 1.5 mg of pancuronium will produce a 90% or greater depression of twitch height. Neostigmine does not reverse the direct effect of enflurane. Enflurane 0.25 to 1.0% (average 0.5%) provides analgesia equal to that produced by 30 to 60% (average 40%) nitrous oxide for vaginal delivery. With either agent, patients remain awake, cooperative and oriented. Maternal blood losses are comparable. These clinical approaches produce normal Apgar scores. Serial neurobehavioral testing of the newborn during the first 24 hours of life reveals that neither enflurane nor nitrous oxide analgesia is associated with obvious neurobehavioral alterations. Neither enflurane nor nitrous oxide when used for obstetrical analgesia alters BUN, creatinine, uric acid or osmolality. The only difference in the use of these two agents for obstetrical analgesia appears to be higher inspired oxygen concentration that may be used with enflurane. Analgetic doses of enflurane, up to approximately 1.0%, do not significantly depress the rate or force of uterine contraction during labor and delivery. A slowing of the rate of uterine contraction and a diminution of the force of uterine contraction is noted between the administration of 1.0 to 2.0% delivered enflurane; concentrations somewhere between 2.0 and 3.0% delivered enflurane may abolish uterine contractions. Enflurane displaces the myometrial response curve to oxytocin so that at lower concentrations of enflurane oxytocin will restore uterine contractions; however, as the dose of enflurane progresses (somewhere between 1.5 and 3.0% delivered enflurane) the response to oxytocin is diminished and then abolished. Uterine bleeding may be increased when enflurane is used in higher concentrations for vaginal delivery or to facilitate delivery by Cesarean section; however, this has not This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-087/S-047 Page 5 been demonstrated within the recommended dosage range (see DOSAGE AND ADMINISTRATION section). Mean estimated blood loss in patients anesthetized for therapeutic termination of pregnancy with 1.0% enflurane in 70% nitrous oxide with oxygen is approximately twice that noted following therapeutic termination of pregnancy performed with the use of a local anesthetic technique (40 mL versus 20 mL). Pharmacokinetics Biotransformation of enflurane in man results in low peak levels of serum fluoride averaging 15 µmol/L. These levels are well below the 50 µmol/L threshold level which can produce minimal renal damage in normal subjects. However, patients chronically ingesting isoniazid or other hydrazine- containing compounds may metabolize greater amounts of enflurane. Although no significant renal dysfunction has been found thus far in such patients, peak serum fluoride levels can exceed 50 µmol/L, particularly when anesthesia goes beyond 2 MAC hours. Depression of lymphocyte transformation does not follow prolonged enflurane anesthesia in man in the absence of surgery. Thus enflurane does not depress this aspect of the immune response. INDICATIONS AND USAGE ĒTHRANE (enflurane, USP) may be used for induction and maintenance of general anesthesia. Enflurane may be used to provide analgesia for vaginal delivery. Low concentrations of enflurane (see DOSAGE AND ADMINISTRATION) may also be used to supplement other general anesthetic agents during delivery by Cesarean section. Higher concentrations of enflurane may produce uterine relaxation and an increase in uterine bleeding. CONTRAINDICATIONS Seizure disorders (see WARNINGS). Known sensitivity to ĒTHRANE (enflurane, USP) or other halogenated anesthetics. Known or suspected genetic susceptibility to malignant hyperthermia. WARNINGS Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-087/S-047 Page 6 not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. Malignant Hyperthermia In susceptible individuals, enflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc. The syndrome of malignant hyperthermia secondary to enflurane appears to be rare; by March 1980, 35 cases had been reported in North America for an approximate incidence of 1:725,000 enflurane anesthetics.) An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of CO2 absorption system (hot cannister). PaO2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., enflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangement. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be sustained if possible. Increasing depth of anesthesia with ĒTHRANE (enflurane, USP) may produce a change in the electroencephalogram characterized by high voltage, fast frequency, progressing through spike-dome complexes alternating with periods of electrical silence to frank seizure activity. The latter may or may not be associated with motor movement. Motor activity, when encountered, generally consists of twitching or “jerks” of various muscle groups; it is self-limiting and can be terminated by lowering the anesthetic concentration. This electroencephalographic pattern associated with deep anesthesia is exacerbated by low arterial carbon dioxide tension. A reduction in ventilation and anesthetic concentrations usually suffices to eliminate seizure activity. Cerebral blood flow and metabolism studies in normal volunteers immediately following seizure activity show no evidence of cerebral hypoxia. Mental function testing does not reveal any impairment of performance following prolonged enflurane anesthesia associated with or not associated with seizure activity. Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used. Hypotension and respiratory exchange can serve as a guide to depth of anesthesia. Deep levels of anesthesia may produce marked hypotension and respiratory depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-087/S-047 Page 7 When previous exposure to a halogenated anesthetic is known to have been followed by evidence of unexplained hepatic dysfunction, consideration should be given to use of an agent other than enflurane. PRECAUTIONS General ĒTHRANE (enflurane, USP) should be used with caution in patients who by virtue of medical or drug history could be considered more susceptible to cortical stimulation produced by the drug. ĒTHRANE (enflurane, USP), like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide which may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 absorber cannister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of ĒTHRANE (enflurane, USP). Information to Patients Enflurane, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 to 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for several days following administration. Laboratory Tests Bromsulfthalein (BSP) retention is mildly elevated postoperatively in some cases. This may relate to the effect of surgery since prolonged anesthesia (5 to 7 hours) in human volunteers does not result in BSP elevation. There is some elevation of glucose and white blood count intraoperatively. Glucose elevation should be considered in diabetic patients. Drug Interactions The action of nondepolarizing relaxants is augmented by enflurane. Less than the usual amounts of these drugs should be used. If the usual amounts of nondepolarizing relaxants are given, the time for recovery from neuromuscular blockade will be longer in the presence of enflurane than when halothane or nitrous oxide with a balanced technique are used. Carcinogenesis/Mutagenesis Swiss ICR mice were given enflurane to determine whether such exposure might induce neoplasia. Enflurane was given at 1/2, 1/8 and 1/32 MAC for four in-utero exposures and for 24 exposures to the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-087/S-047 Page 8 pups during the first nine weeks of life. The mice were killed at 15 months of age. The incidence of tumors in these mice was the same as in untreated control mice who were given the same background gases, but not the anesthetic. Exposure of mice to 20 hours of 1.2% enflurane causes a small (about 1/2 of 1.0%) but statistically significant increase in sperm abnormalities. In contrast to these results, in vitro approaches to the study of mutagenesis (Ames test, sister chromatid exchange test, and the 8-azaguanine system) have not shown a mutagenic effect of enflurane. Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to enflurane. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when enflurane is administered to a nursing woman. ADVERSE REACTIONS 1. Malignant hyperthermia (see WARNINGS). 2. Motor activity exemplified by movements of various muscle groups and/or seizures may be encountered with deep levels of ĒTHRANE (enflurane, USP) anesthesia, or light levels with hypocapnia. 3. Hypotension, respiratory depression, and hypoxia have been reported. 4. Arrhythmias, shivering, nausea and vomiting have been reported. 5. Elevation of the white blood count has been observed. 6. Mild, moderate and severe liver injury, including hepatic failure, may rarely follow anesthesia with enflurane. Serum transaminases may be increased and histologic evidence of injury may be found. The histologic changes are neither unique nor consistent. In several of these cases, it has not been possible to exclude enflurane as the cause or as a contributing cause to liver injury. The incidence of unexplained hepatotoxicity following the administration of enflurane is unknown, but it appears to be rare and not dose related. ĒTHRANE (enflurane, USP) has also been associated with perioperative hyperkalemia (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-087/S-047 Page 9 There have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile anesthetic agents, including ĒTHRANE (enflurane, USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of ĒTHRANE (enflurane, USP) to these events cannot be established with certainty. OVERDOSAGE In the event of overdosage, or what may appear to be overdosage, the following action should be taken: Stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen. DOSAGE AND ADMINISTRATION The concentration of ĒTHRANE (enflurane, USP) being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using: 1. vaporizers calibrated specifically for enflurane; 2. vaporizers from which delivered flows can easily and readily be calculated. Preanesthetic Medication Preanesthetic medication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by enflurane and that enflurane does not alter heart rate. The use of anticholinergic drugs is a matter of choice. Surgical Anesthesia Induction may be achieved using enflurane alone with oxygen or in combination with oxygen-nitrous oxide mixtures. Under these conditions some excitement may be encountered. If excitement is to be avoided, a hypnotic dose of a short-acting barbiturate should be used to induce unconsciousness, followed by the enflurane mixture. In general, inspired concentrations of 2.0 to 4.5% enflurane produce surgical anesthesia in 7 to 10 minutes. Maintenance Surgical levels of anesthesia may be maintained with 0.5 to 3.0% enflurane. Maintenance concentrations should not exceed 3.0%. If added relaxation is required, supplemental doses of muscle relaxants may be used. Ventilation to maintain the tension of carbon dioxide in arterial blood in the 35 to 45 mm Hg range is preferred. Hyperventilation should be avoided in order to minimize possible CNS excitation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-087/S-047 Page 10 The level of blood pressure during maintenance is an inverse function of enflurane concentration in the absence of other complicating problems. Excessive decreases (unless related to hypovolemia) may be due to depth of anesthesia and in such instances should be corrected by lightening the level of anesthesia. Analgesia Enflurane 0.25 to 1.0% provides analgesia for vaginal delivery equal to that produced by 30 to 60% nitrous oxide. These concentrations normally do not produce amnesia. See also the information on the effects of enflurane on uterine contraction contained in the CLINICAL PHARMACOLOGY section. Cesarean Section Enflurane should ordinarily be administered in the concentration range of 0.5 to 1.0% to supplement other general anesthetics. See also the information on the effects of enflurane on uterine contraction contained in the CLINICAL PHARMACOLOGY section. HOW SUPPLIED ĒTHRANE (enflurane, USP) is packaged in 125 and 250 mL amber-colored bottles. 125 mL — NDC 10019-350-50 250 mL — NDC 10019-350-60 Safety and Handling Occupational Caution There is no specific work exposure limit established for ĒTHRANE (enflurane, USP). However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour. The predicted effects of acute overexposure by inhalation of ĒTHRANE (enflurane, USP) include headache, dizziness or (in extreme cases) unconsciousness. There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors (Waste Anesthetic Gases or WAGs) in the workplace. Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive. Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-087/S-047 Page 11 Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks. Storage Store at room temperature 15º-30ºC (59º-86ºF). Enflurane contains no additives and has been demonstrated to be stable at room temperature for periods in excess of five years. Baxter and ĒTHRANE are trademarks of Baxter International Inc. registered in the United States Patent and Trademark Office. Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) Revised: July 2006 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:08.178467	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017087s047lbl.pdf', 'application_number': 17087, 'submission_type': 'SUPPL ', 'submission_number': 47}
10,963	Ethrane® (enflurane, USP) Page 1 of 9 ĒTHRANE (enflurane, USP) Liquid For Inhalation Rx only DESCRIPTION ĒTHRANE (enflurane, USP), a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether (CHF2OCF2CHFCl). The boiling point is 56.5ºC at 760 mm Hg, and the vapor pressure (in mm Hg) is 175 at 20ºC, 218 at 25ºC, and 345 at 36ºC. Vapor pressures can be calculated using the equation: A = 7.967 log10Pvap = A + B/T B = -1678.4 T = ºC + 273.16 (Kelvin) The specific gravity (25º/25ºC) is 1.517. The refractive index at 20ºC is 1.3026-1.3030. The blood/gas coefficient is 1.91 at 37ºC and the oil/gas coefficient is 98.5 at 37ºC. Enflurane is a clear, colorless, stable liquid whose purity exceeds 99.9% (area percent by gas chromatography). No stabilizers are added as these have been found, through controlled laboratory tests, to be unnecessary even in the presence of ultraviolet light. Enflurane is stable to strong base, does not decompose in contact with soda lime (at normal operating temperatures), and does not react with aluminum, tin, brass, iron or copper. The partition coefficients of enflurane at 25ºC are 74 in conductive rubber and 120 in polyvinyl chloride. CLINICAL PHARMACOLOGY ĒTHRANE (enflurane, USP) is an inhalation anesthetic. The MAC (minimum alveolar concentration) in man is 1.68% in pure oxygen, 0.57 in 70% nitrous oxide, 30% oxygen, and 1.17 in 30% nitrous oxide, 70% oxygen. Induction of and recovery from anesthesia with enflurane are rapid. Enflurane has a mild, sweet odor. Enflurane may provide a mild stimulus to salivation or tracheobronchial secretions. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia can be changed rapidly by changing the inspired enflurane concentration. Enflurane reduces ventilation as depth of anesthesia increases. High PaCO2 levels can be obtained at deeper levels of anesthesia if ventilation is not supported. Enflurane provokes a sigh response reminiscent of that seen with diethyl ether. There is a decrease in blood pressure with induction of anesthesia, followed by a return to near normal with surgical stimulation. Progressive increases in depth of anesthesia produce 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ethrane® (enflurane, USP) Page 2 of 9 corresponding increases in hypotension. Heart rate remains relatively constant without significant bradycardia. Electrocardiographic monitoring or recordings indicate that cardiac rhythm remains stable. Elevation of the carbon dioxide level in arterial blood does not alter cardiac rhythm. Studies in man indicate a considerable margin of safety in the administration of epinephrine- containing solutions during enflurane anesthesia. Enflurane anesthesia has been used in excision of pheochromocytoma in man without ventricular arrhythmias. On the basis of studies in patients anesthetized with enflurane and injected with epinephrine-containing solutions to achieve hemostasis in a highly vascular area (transsphenoidal surgery), up to 2 micrograms per kilogram (2 μg/kg) of epinephrine may be injected subcutaneously over a 10 minute period in patients judged to have ordinary tolerance to epinephrine administration. This would represent up to 14 mL of 1:100,000 epinephrine-containing solution (10 μg/mL), or the equivalent quantity, in a 70 kilogram patient. This may be repeated up to 3 times per hour (total 42 mL per hour). The concomitant administration of lidocaine enhances the safety of the use of epinephrine during enflurane anesthesia. This effect of lidocaine is dose related. All customary precautions in the use of vasoconstrictor substances should be observed. Muscle relaxation may be adequate for intra-abdominal operations at normal levels of anesthesia. Muscle relaxants may be used to achieve greater relaxation and all commonly used muscle relaxants are compatible with enflurane. THE NON-DEPOLARIZING MUSCLE RELAXANTS ARE POTENTIATED. In the normal 70 kg adult, 6 to 9 mg of d-tubocurarine or 1.0 to 1.5 mg of pancuronium will produce a 90% or greater depression of twitch height. Neostigmine does not reverse the direct effect of enflurane. Enflurane 0.25 to 1.0% (average 0.5%) provides analgesia equal to that produced by 30 to 60% (average 40%) nitrous oxide for vaginal delivery. With either agent, patients remain awake, cooperative and oriented. Maternal blood losses are comparable. These clinical approaches produce normal Apgar scores. Serial neurobehavioral testing of the newborn during the first 24 hours of life reveals that neither enflurane nor nitrous oxide analgesia is associated with obvious neurobehavioral alterations. Neither enflurane nor nitrous oxide when used for obstetrical analgesia alters BUN, creatinine, uric acid or osmolality. The only difference in the use of these two agents for obstetrical analgesia appears to be higher inspired oxygen concentration that may be used with enflurane. Analgetic doses of enflurane, up to approximately 1.0%, do not significantly depress the rate or force of uterine contraction during labor and delivery. A slowing of the rate of uterine contraction and a diminution of the force of uterine contraction is noted between the administration of 1.0 to 2.0% delivered enflurane; concentrations somewhere between 2.0 and 3.0% delivered enflurane may abolish uterine contractions. Enflurane displaces the myometrial response curve to oxytocin so that at lower concentrations of enflurane oxytocin will restore uterine contractions; however, as the 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ethrane® (enflurane, USP) Page 3 of 9 dose of enflurane progresses (somewhere between 1.5 and 3.0% delivered enflurane) the response to oxytocin is diminished and then abolished. Uterine bleeding may be increased when enflurane is used in higher concentrations for vaginal delivery or to facilitate delivery by Cesarean section; however, this has not been demonstrated within the recommended dosage range (see DOSAGE AND ADMINISTRATION section). Mean estimated blood loss in patients anesthetized for therapeutic termination of pregnancy with 1.0% enflurane in 70% nitrous oxide with oxygen is approximately twice that noted following therapeutic termination of pregnancy performed with the use of a local anesthetic technique (40 mL versus 20 mL). Pharmacokinetics Biotransformation of enflurane in man results in low peak levels of serum fluoride averaging 15 μmol/L. These levels are well below the 50 μmol/L threshold level which can produce minimal renal damage in normal subjects. However, patients chronically ingesting isoniazid or other hydrazine-containing compounds may metabolize greater amounts of enflurane. Although no significant renal dysfunction has been found thus far in such patients, peak serum fluoride levels can exceed 50 μmol/L, particularly when anesthesia goes beyond 2 MAC hours. Depression of lymphocyte transformation does not follow prolonged enflurane anesthesia in man in the absence of surgery. Thus enflurane does not depress this aspect of the immune response. INDICATIONS AND USAGE ĒTHRANE (enflurane, USP) may be used for induction and maintenance of general anesthesia. Enflurane may be used to provide analgesia for vaginal delivery. Low concentrations of enflurane (see DOSAGE AND ADMINISTRATION) may also be used to supplement other general anesthetic agents during delivery by Cesarean section. Higher concentrations of enflurane may produce uterine relaxation and an increase in uterine bleeding. CONTRAINDICATIONS Seizure disorders (see WARNINGS). Known sensitivity to ĒTHRANE (enflurane, USP) or other halogenated anesthetics. Known or suspected genetic susceptibility to malignant hyperthermia. WARNINGS Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ethrane® (enflurane, USP) Page 4 of 9 muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. Malignant Hyperthermia In susceptible individuals, enflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc. The syndrome of malignant hyperthermia secondary to enflurane appears to be rare; by March 1980, 35 cases had been reported in North America for an approximate incidence of 1:725,000 enflurane anesthetics.) An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of CO2 absorption system (hot cannister). PaO2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., enflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangement. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be sustained if possible. Increasing depth of anesthesia with ĒTHRANE (enflurane, USP) may produce a change in the electroencephalogram characterized by high voltage, fast frequency, progressing through spike- dome complexes alternating with periods of electrical silence to frank seizure activity. The latter may or may not be associated with motor movement. Motor activity, when encountered, generally consists of twitching or “jerks” of various muscle groups; it is self-limiting and can be terminated by lowering the anesthetic concentration. This electroencephalographic pattern associated with deep anesthesia is exacerbated by low arterial carbon dioxide tension. A reduction in ventilation and anesthetic concentrations usually suffices to eliminate seizure activity. Cerebral blood flow and metabolism studies in normal volunteers immediately following seizure activity show no evidence of cerebral hypoxia. Mental function testing does not reveal any impairment of performance following prolonged enflurane anesthesia associated with or not associated with seizure activity. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ethrane® (enflurane, USP) Page 5 of 9 Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used. Hypotension and respiratory exchange can serve as a guide to depth of anesthesia. Deep levels of anesthesia may produce marked hypotension and respiratory depression. When previous exposure to a halogenated anesthetic is known to have been followed by evidence of unexplained hepatic dysfunction, consideration should be given to use of an agent other than enflurane. PRECAUTIONS General ĒTHRANE (enflurane, USP) should be used with caution in patients who by virtue of medical or drug history could be considered more susceptible to cortical stimulation produced by the drug. ĒTHRANE (enflurane, USP), like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide which may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 absorber cannister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of ĒTHRANE (enflurane, USP). Information to Patients Enflurane, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 to 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for several days following administration. Laboratory Tests Bromsulfthalein (BSP) retention is mildly elevated postoperatively in some cases. This may relate to the effect of surgery since prolonged anesthesia (5 to 7 hours) in human volunteers does not result in BSP elevation. There is some elevation of glucose and white blood count intraoperatively. Glucose elevation should be considered in diabetic patients. Drug Interactions The action of nondepolarizing relaxants is augmented by enflurane. Less than the usual amounts of these drugs should be used. If the usual amounts of nondepolarizing relaxants are given, the time for recovery from neuromuscular blockade will be longer in the presence of enflurane than when halothane or nitrous oxide with a balanced technique are used. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ethrane® (enflurane, USP) Page 6 of 9 Carcinogenesis/Mutagenesis Swiss ICR mice were given enflurane to determine whether such exposure might induce neoplasia. Enflurane was given at 1/2, 1/8 and 1/32 MAC for four in-utero exposures and for 24 exposures to the pups during the first nine weeks of life. The mice were killed at 15 months of age. The incidence of tumors in these mice was the same as in untreated control mice who were given the same background gases, but not the anesthetic. Exposure of mice to 20 hours of 1.2% enflurane causes a small (about 1/2 of 1.0%) but statistically significant increase in sperm abnormalities. In contrast to these results, in vitro approaches to the study of mutagenesis (Ames test, sister chromatid exchange test, and the 8-azaguanine system) have not shown a mutagenic effect of enflurane. Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to enflurane. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when enflurane is administered to a nursing woman. ADVERSE REACTIONS 1. Malignant hyperthermia (see WARNINGS). 2. Motor activity exemplified by movements of various muscle groups and/or seizures may be encountered with deep levels of ĒTHRANE (enflurane, USP) anesthesia, or light levels with hypocapnia. 3. Hypotension, respiratory depression, and hypoxia have been reported. 4. Arrhythmias, shivering, nausea and vomiting have been reported. 5. Elevation of the white blood count has been observed. 6. Mild, moderate and severe liver injury, including hepatic failure, may rarely follow anesthesia with enflurane. Serum transaminases may be increased and histologic evidence of injury may be found. The histologic changes are neither unique nor consistent. In several of these cases, it has not been possible to exclude enflurane as the cause or as a contributing cause to liver injury. The incidence of unexplained hepatotoxicity following the administration of enflurane is unknown, but it appears to be rare and not dose related. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ethrane® (enflurane, USP) Page 7 of 9 ĒTHRANE (enflurane, USP) has also been associated with perioperative hyperkalemia (see WARNINGS). Post-Marketing Events The following adverse events have been identified during post-approval use of ĒTHRANE (enflurane, USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of ĒTHRANE (enflurane, USP) to these events cannot be established with certainty. Cardiac Disorders: Cardiac arrest Hepatobiliary Disorders: Hepatic necrosis, Hepatic failure OVERDOSAGE In the event of overdosage, or what may appear to be overdosage, the following action should be taken: Stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen. DOSAGE AND ADMINISTRATION The concentration of ĒTHRANE (enflurane, USP) being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using: a. vaporizers calibrated specifically for enflurane; b. vaporizers from which delivered flows can easily and readily be calculated. Preanesthetic Medication Preanesthetic medication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by enflurane and that enflurane does not alter heart rate. The use of anticholinergic drugs is a matter of choice. Surgical Anesthesia Induction may be achieved using enflurane alone with oxygen or in combination with oxygen- nitrous oxide mixtures. Under these conditions some excitement may be encountered. If excitement is to be avoided, a hypnotic dose of a short-acting barbiturate should be used to induce unconsciousness, followed by the enflurane mixture. In general, inspired concentrations of 2.0 to 4.5% enflurane produce surgical anesthesia in 7 to 10 minutes. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ethrane® (enflurane, USP) Page 8 of 9 Maintenance Surgical levels of anesthesia may be maintained with 0.5 to 3.0% enflurane. Maintenance concentrations should not exceed 3.0%. If added relaxation is required, supplemental doses of muscle relaxants may be used. Ventilation to maintain the tension of carbon dioxide in arterial blood in the 35 to 45 mm Hg range is preferred. Hyperventilation should be avoided in order to minimize possible CNS excitation. The level of blood pressure during maintenance is an inverse function of enflurane concentration in the absence of other complicating problems. Excessive decreases (unless related to hypovolemia) may be due to depth of anesthesia and in such instances should be corrected by lightening the level of anesthesia. Analgesia Enflurane 0.25 to 1.0% provides analgesia for vaginal delivery equal to that produced by 30 to 60% nitrous oxide. These concentrations normally do not produce amnesia. See also the information on the effects of enflurane on uterine contraction contained in the CLINICAL PHARMACOLOGY section. Cesarean Section Enflurane should ordinarily be administered in the concentration range of 0.5 to 1.0% to supplement other general anesthetics. See also the information on the effects of enflurane on uterine contraction contained in the CLINICAL PHARMACOLOGY section. HOW SUPPLIED ĒTHRANE (enflurane, USP) is packaged in 125 and 250 mL amber-colored bottles. 125 mL — NDC 10019-350-50 250 mL — NDC 10019-350-60 Safety and Handling Occupational Caution There is no specific work exposure limit established for ĒTHRANE (enflurane, USP). However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ethrane® (enflurane, USP) Page 9 of 9 The predicted effects of acute overexposure by inhalation of ĒTHRANE (enflurane, USP) include headache, dizziness or (in extreme cases) unconsciousness. There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors (Waste Anesthetic Gases or WAGs) in the workplace. Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive. Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks. Storage Store at room temperature 15º-30ºC (59º-86ºF). Enflurane contains no additives and has been demonstrated to be stable at room temperature for periods in excess of five years. Baxter and ĒTHRANE are trademarks of Baxter International Inc. registered in the United States Patent and Trademark Office. Company logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT 00088/3.0 Revised: January 2010 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:08.245944	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017087s048lbl.pdf', 'application_number': 17087, 'submission_type': 'SUPPL ', 'submission_number': 48}
10,964	Page 1 of 15 Tofranil-PM® imipramine pamoate capsules (75 mg, 100 mg, 125 mg and 150 mg) For oral administration Rx only Prescribing Information Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of imipramine pamoate or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Imipramine pamoate is not approved for use in pediatric patients (see WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use). DESCRIPTION Tofranil-PM® (imipramine pamoate capsules), is a tricyclic antidepressant, available as capsules for oral administration. The 75-, 100-, 125-, and 150-mg capsules contain imipramine pamoate equivalent to 75, 100, 125, and 150 mg of imipramine hydrochloride. Imipramine pamoate is 5- [3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine 4, 4'-methylenebis-(3-hydroxy- 2-naphthoate) (2:1), and its structural formula is (C19H24N2)2●C23H16O6 M.W. = 949.21 Imipramine pamoate is a fine, yellow, tasteless, odorless powder. It is soluble in ethanol, in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 of 15 acetone, in ether, in chloroform, and in carbon tetrachloride, and is insoluble in water. Inactive Ingredients. D&C Red No. 28, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 (100 mg and 125 mg capsules only), gelatin, magnesium stearate, parabens, starch, talc, and titanium dioxide. CLINICAL PHARMACOLOGY The mechanism of action of imipramine is not definitely known. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings. INDICATIONS AND USAGE For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident. CONTRAINDICATIONS The concomitant use of monoamine oxidase inhibiting compounds is contraindicated. Hyperpyretic crises or severe convulsive seizures may occur in patients receiving such combinations. The potentiation of adverse effects can be serious, or even fatal. When it is desired to substitute Tofranil-PM® in patients receiving a monoamine oxidase inhibitor, as long an interval should elapse as the clinical situation will allow, with a minimum of 14 days. Initial dosage should be low and increases should be gradual and cautiously prescribed. The drug is contraindicated during the acute recovery period after a myocardial infarction. Patients with a known hypersensitivity to this compound should not be given the drug. The possibility of cross-sensitivity to other dibenzazepine compounds should be kept in mind. WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 of 15 disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short- term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo- controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short- term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 of 15 Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for imipramine pamoate should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder – A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that imipramine pamoate is not approved for use in treating bipolar depression. Extreme caution should be used when this drug is given to patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes, and tachycardia. These patients require cardiac surveillance at all dosage levels of the drug; patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold; patients receiving guanethidine, clonidine, or similar agents, since imipramine pamoate may block the pharmacologic effects of these drugs; patients receiving methylphenidate hydrochloride. Since methylphenidate hydrochloride may inhibit the metabolism of imipramine pamoate, downward dosage adjustment of imipramine pamoate may be required when given concomitantly with methylphenidate hydrochloride. Since imipramine pamoate may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly. Tofranil-PM® (imipramine pamoate capsules) may enhance the CNS depressant effects of alcohol. Therefore, it should be borne in mind that the dangers inherent in a suicide attempt or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 of 15 accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol. (See PRECAUTIONS.) PRECAUTIONS General An ECG recording should be taken prior to the initiation of larger-than-usual doses of imipramine pamoate and at appropriate intervals thereafter until steady state is achieved. (Patients with any evidence of cardiovascular disease require cardiac surveillance at all dosage levels of the drug. See WARNINGS.) Elderly patients and patients with cardiac disease or a prior history of cardiac disease are at special risk of developing the cardiac abnormalities associated with the use of imipramine pamoate. It should be kept in mind that the possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Such patients should be carefully supervised during the early phase of treatment with imipramine pamoate and may require hospitalization. Prescriptions should be written for the smallest amount feasible. Hypomanic or manic episodes may occur, particularly in patients with cyclic disorders. Such reactions may necessitate discontinuation of the drug. If needed, imipramine pamoate may be resumed in lower dosage when these episodes are relieved. Administration of a tranquilizer may be useful in controlling such episodes. An activation of the psychosis may occasionally be observed in schizophrenic patients and may require reduction of dosage and the addition of a phenothiazine. Concurrent administration of imipramine pamoate with electroshock therapy may increase the hazards: such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience. Patients taking imipramine pamoate should avoid excessive exposure to sunlight since there have been reports of photosensitization. Both elevation and lowering of blood sugar levels have been reported with imipramine pamoate use. Imipramine pamoate should be used with caution in patients with significantly impaired renal or hepatic function. Patients who develop a fever and a sore throat during therapy with imipramine pamoate should have leukocyte and differential blood counts performed. Imipramine pamoate should be discontinued if there is evidence of pathological neutrophil depression. Prior to elective surgery, imipramine pamoate should be discontinued for as long as the clinical situation will allow. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 of 15 Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with imipramine pamoate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for imipramine pamoate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking imipramine pamoate. Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day- to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Drug Interactions Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8- fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 of 15 involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary. In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents) in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus). Close supervision and careful adjustment of dosage is required when imipramine pamoate is administered concomitantly with anticholinergic drugs. Avoid the use of preparations, such as decongestants and local anesthetics, that contain any sympathomimetic amine (e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Caution should be exercised when imipramine pamoate is used with agents that lower blood pressure. Imipramine pamoate may potentiate the effects of CNS depressant drugs. Patients should be warned that imipramine pamoate may enhance the CNS depressant effects of alcohol. (See WARNINGS.) Pregnancy Animal reproduction studies have yielded inconclusive results. (See also ANIMAL PHARMACOLOGY & TOXICOLOGY.) There have been no well-controlled studies conducted with pregnant women to determine the effect of imipramine on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of imipramine cannot be excluded. Therefore, imipramine should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus. Nursing Mothers Limited data suggest that imipramine is likely to be excreted in human breast milk. As a general This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 of 15 rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk). It is generally recommended that Tofranil-PM® should not be used in children because of the increased potential for acute overdosage due to the high unit potency (75 mg, 100 mg, 125 mg, and 150 mg). Each capsule contains imipramine pamoate equivalent to 75 mg, 100 mg, 125 mg, or 150 mg imipramine hydrochloride. Anyone considering the use of imipramine pamoate in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with Tofranil® in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There were no additional adverse experiences identified in the elderly. Clinical studies of Tofranil® in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (see also DOSAGE AND ADMINISTRATION in Adolescent and Geriatric Patients) (see also PRECAUTIONS General) ADVERSE REACTIONS Note: Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when imipramine is administered. Cardiovascular: Orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke. Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis. Neurological: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 of 15 peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus. Anticholinergic: Dry mouth, and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. Allergic: Skin rash, petechiae, urticaria, itching, photosensitization; edema (general or of face and tongue); drug fever; cross-sensitivity with desipramine. Hematologic: Bone marrow depression including agranulocytosis; eosinophilia; purpura; thrombocytopenia. Gastrointestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue. Endocrine: Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; inappropriate antidiuretic hormone (ADH) secretion syndrome. Other: Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling. Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache and malaise. OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible. Children have been reported to be more sensitive than adults to an acute overdosage of imipramine pamoate. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal. Manifestations These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 of 15 hyperactive reflexes, muscle rigidity, athetoid and choreiform movements. Cardiac abnormalities may include tachycardia, and signs of congestive failure. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present. Management Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination – All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular – A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.60 or a pCO2 < 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning. CNS – In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 of 15 Pediatric Management – The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. DOSAGE AND ADMINISTRATION The following recommended dosages for Tofranil-PM® (imipramine pamoate capsules) should be modified as necessary by the clinical response and any evidence of intolerance. Initial Adult Dosage Outpatients – Therapy should be initiated at 75 mg/day. Dosage may be increased to 150 mg/day which is the dose level at which optimum response is usually obtained. If necessary, dosage may be increased to 200 mg/day. Dosage higher than 75 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Hospitalized Patients – Therapy should be initiated at 100 to 150 mg/day and may be increased to 200 mg/day. If there is no response after two weeks, dosage should be increased to 250 to 300 mg/day. Dosage higher than 150 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Adult Maintenance Dosage – Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased. The usual maintenance dosage is 75 to 150 mg/day. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted. Adolescent and Geriatric Patients – Therapy in these age groups should be initiated with Tofranil®, brand of imipramine hydrochloride, tablets at a total daily dosage of 25 to 50 mg, since Tofranil-PM® capsules are not available in these strengths. Dosage may be increased according This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 of 15 to response and tolerance, but it is generally unnecessary to exceed 100 mg/day in these patients. Tofranil-PM® capsules may be used when total daily dosage is established at 75 mg or higher. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Adolescent and geriatric patients can usually be maintained at lower dosage. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased. The total daily maintenance dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted. HOW SUPPLIED Tofranil-PM® (imipramine pamoate capsules) Capsules 75 mg – coral body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 75 mg”. Bottles of 30 …………….NDC 0406-9923-03 Capsules 100 mg – maize body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 100 mg”. Bottles of 30……….…….NDC 0406-9924-03 Capsules 125 mg – ivory body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 125 mg”. Bottles of 30……….…….NDC 0406-9925-03 Capsules 150 mg – coral body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 150 mg”. Bottles of 30………..…….NDC 0406-9926-03 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in tight container (USP) with a child-resistant closure. ANIMAL PHARMACOLOGY & TOXICOLOGY A. Acute: Oral LD50: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 of 15 Mouse 2185 mg/kg Rat (F) 1142 mg/kg (M) 1807 mg/kg Rabbit 1016 mg/kg Dog 693 mg/kg (Emesis ED50) B. Subacute: Two three-month studies in dogs gave evidence of an adverse drug effect on the testes, but only at the highest dose level employed, i.e., 90 mg/kg (10 times the maximum human dose). Depending on the histological section of the testes examined, the findings consisted of a range of degenerative changes up to and including complete atrophy of the seminiferous tubules, with spermatogenesis usually arrested. Human studies show no definitive effect on sperm count, sperm motility, sperm morphology or volume of ejaculate. Rat One three-month study was done in rats at dosage levels comparable to those of the dog studies. No adverse drug effect on the testes was noted in this study, as confirmed by histological examination. C. Reproduction/Teratogenic: Oral: Imipramine pamoate was fed to male and female albino rats for 28 weeks through two breeding cycles at dose levels of 15 mg/kg/day and 40 mg/kg/day (equivalent to 2 1/2 and 7 times the maximum human dose). No abnormalities which could be related to drug administration were noted in gross inspection. Autopsies performed on pups from the second breeding likewise revealed no pathological changes in organs or tissues; however, a decrease in mean litter size from both matings was noted in the drug-treated groups and significant growth suppression occurred in the nursing pups of both sexes in the high group as well as in the females of the low-level group. Finally, the lactation index (pups weaned divided by number left to nurse) was significantly lower in the second litter of the high- level group. Tofranil and Tofranil-PM are registered trademarks of Mallinckrodt Inc. M is a registered trademark of Mallinckrodt Inc. Manufactured by Patheon Inc. Whitby, Ontario, Canada L1N 5Z5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 of 15 Manufactured for Mallinckrodt Inc. Hazelwood, MO 63042 U.S.A. Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 of 15 • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Mallinckrodt Inc. Hazelwood, MO 63042 U.S.A. Rev 050707 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:08.342645	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017090s74lbl.pdf', 'application_number': 17090, 'submission_type': 'SUPPL ', 'submission_number': 74}
10,966	Tofranil-PM™ (imipramine pamoate) capsules (75 mg, 100 mg, 125 mg and 150 mg) For oral administration Rx only Prescribing Information Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of imipramine pamoate or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Imipramine pamoate is not approved for use in pediatric patients (see WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use). DESCRIPTION Tofranil-PM™ (imipramine pamoate) capsules are a tricyclic antidepressant, available as capsules for oral administration. The 75-, 100-, 125-, and 150-mg capsules contain imipramine pamoate equivalent to 75, 100, 125, and 150 mg of imipramine hydrochloride. Imipramine pamoate is 5-[3-(dimethylamino)propyl]-10,11-dihydro-5H dibenz[b,f]azepine 4, 4'-methylenebis-(3-hydroxy-2-naphthoate) (2:1), and its structural formula is structural formula (C19H24N2)2●C23H16O6 M.W. = 949.21 Page 1 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Imipramine pamoate is a fine, yellow, tasteless, odorless powder. It is soluble in ethanol, in acetone, in ether, in chloroform, and in carbon tetrachloride, and is insoluble in water. Inactive Ingredients. D&C Red No. 28, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 (100 mg and 125 mg capsules only), gelatin, magnesium stearate, parabens, starch, talc, and titanium dioxide. CLINICAL PHARMACOLOGY The mechanism of action of imipramine is not definitely known. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings. INDICATIONS AND USAGE For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident. CONTRAINDICATIONS Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with Tofranil-PM or within 14 days of stopping treatment with Tofranil-PM is contraindicated because of an increased risk of serotonin syndrome. The use of Tofranil-PM within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). Starting Tofranil-PM in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION). Myocardial Infarction The drug is contraindicated during the acute recovery period after a myocardial infarction. Hypersensitivity to Tricyclic Antidepressants Patients with a known hypersensitivity to this compound should not be given the drug. The possibility of cross-sensitivity to other dibenzazepine compounds should be kept in mind. Page 2 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long- standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 18-24 14 additional cases 5 additional cases Decreases Compared to Placebo 25-64 ≥65 1 fewer case 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. Page 3 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for imipramine pamoate should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder – A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should Page 4 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be noted that imipramine pamoate is not approved for use in treating bipolar depression. Extreme caution should be used when this drug is given to patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes, and tachycardia. These patients require cardiac surveillance at all dosage levels of the drug; patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold; patients receiving guanethidine, clonidine, or similar agents, since imipramine pamoate may block the pharmacologic effects of these drugs; patients receiving methylphenidate hydrochloride. Since methylphenidate hydrochloride may inhibit the metabolism of imipramine pamoate, downward dosage adjustment of imipramine pamoate may be required when given concomitantly with methylphenidate hydrochloride. Since imipramine pamoate may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly. Tofranil-PM may enhance the CNS depressant effects of alcohol. Therefore, it should be borne in mind that the dangers inherent in a suicide attempt or accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol (see PRECAUTIONS). Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Tofranil-PM, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of Tofranil-PM with MAOIs intended to treat psychiatric disorders is contraindicated. Tofranil-PM should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved Page 5 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Tofranil-PM. Tofranil-PM should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of Tofranil-PM with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Tofranil-PM and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Tofranil-PM may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. PRECAUTIONS General An ECG recording should be taken prior to the initiation of larger-than-usual doses of imipramine pamoate and at appropriate intervals thereafter until steady state is achieved. (Patients with any evidence of cardiovascular disease require cardiac surveillance at all dosage levels of the drug. See WARNINGS.) Elderly patients and patients with cardiac disease or a prior history of cardiac disease are at special risk of developing the cardiac abnormalities associated with the use of imipramine pamoate. It should be kept in mind that the possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Such patients should be carefully supervised during the early phase of treatment with imipramine pamoate and may require hospitalization. Prescriptions should be written for the smallest amount feasible. Hypomanic or manic episodes may occur, particularly in patients with cyclic disorders. Such reactions may necessitate discontinuation of the drug. If needed, imipramine pamoate may be resumed in lower dosage when these episodes are relieved. Administration of a tranquilizer may be useful in controlling such episodes. An activation of the psychosis may occasionally be observed in schizophrenic patients and may require reduction of dosage and the addition of a phenothiazine. Page 6 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concurrent administration of imipramine pamoate with electroshock therapy may increase the hazards: such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience. Patients taking imipramine pamoate should avoid excessive exposure to sunlight since there have been reports of photosensitization. Both elevation and lowering of blood sugar levels have been reported with imipramine pamoate use. Imipramine pamoate should be used with caution in patients with significantly impaired renal or hepatic function. Patients who develop a fever and a sore throat during therapy with imipramine pamoate should have leukocyte and differential blood counts performed. Imipramine pamoate should be discontinued if there is evidence of pathological neutrophil depression. Prior to elective surgery, imipramine pamoate should be discontinued for as long as the clinical situation will allow. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with imipramine pamoate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for imipramine pamoate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking imipramine pamoate. Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of Page 7 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be advised that taking Tofranil-PM can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Drug Interactions Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Page 8 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary. In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents) in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus). Close supervision and careful adjustment of dosage is required when imipramine pamoate is administered concomitantly with anticholinergic drugs. Avoid the use of preparations, such as decongestants and local anesthetics, that contain any sympathomimetic amine (e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Caution should be exercised when imipramine pamoate is used with agents that lower blood pressure. Imipramine pamoate may potentiate the effects of CNS depressant drugs. Patients should be warned that imipramine pamoate may enhance the CNS depressant effects of alcohol (see WARNINGS). Monoamine Oxidase Inhibitors (MAOIs) (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Serotonergic Drugs (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Pregnancy Animal reproduction studies have yielded inconclusive results (see also ANIMAL PHARMACOLOGY & TOXICOLOGY). There have been no well-controlled studies conducted with pregnant women to determine the effect of imipramine on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of imipramine cannot be excluded. Therefore, imipramine should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus. Nursing Mothers Limited data suggest that imipramine is likely to be excreted in human breast milk. As a general rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child. Page 9 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). It is generally recommended that Tofranil-PM should not be used in children because of the increased potential for acute overdosage due to the high unit potency (75 mg, 100 mg, 125 mg, and 150 mg). Each capsule contains imipramine pamoate equivalent to 75 mg, 100 mg, 125 mg, or 150 mg imipramine hydrochloride. Anyone considering the use of imipramine pamoate in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with Tofranil™ , brand of imipramine hydrochloride tablets, in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There were no additional adverse experiences identified in the elderly. Clinical studies of Tofranil™, brand of imipramine hydrochloride tablets, in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See also DOSAGE AND ADMINISTRATION, Adolescent and Geriatric Patients) (See also PRECAUTIONS, General) ADVERSE REACTIONS Note: Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when imipramine is administered. Cardiovascular: Orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke. Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis. Page 10 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Neurological: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus. Anticholinergic: Dry mouth, and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. Allergic: Skin rash, petechiae, urticaria, itching, photosensitization; edema (general or of face and tongue); drug fever; cross-sensitivity with desipramine. Hematologic: Bone marrow depression including agranulocytosis; eosinophilia; purpura; thrombocytopenia. Gastrointestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue. Endocrine: Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; inappropriate antidiuretic hormone (ADH) secretion syndrome. Other: Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling. Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache and malaise. OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible. Children have been reported to be more sensitive than adults to an acute overdosage of imipramine pamoate. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal. Manifestations These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. Critical manifestations of overdose include cardiac dysrhythmias, severe Page 11 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements. Cardiac abnormalities may include tachycardia, and signs of congestive failure. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present. Management Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination – All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular – A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning. CNS – In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, Page 12 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management – The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. DOSAGE AND ADMINISTRATION The following recommended dosages for Tofranil-PM should be modified as necessary by the clinical response and any evidence of intolerance. Initial Adult Dosage Outpatients – Therapy should be initiated at 75 mg/day. Dosage may be increased to 150 mg/day which is the dose level at which optimum response is usually obtained. If necessary, dosage may be increased to 200 mg/day. Dosage higher than 75 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Hospitalized Patients – Therapy should be initiated at 100 to 150 mg/day and may be increased to 200 mg/day. If there is no response after two weeks, dosage should be increased to 250 to 300 mg/day. Dosage higher than 150 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Adult Maintenance Dosage – Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased. Page 13 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The usual maintenance dosage is 75 to 150 mg/day. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted. Adolescent and Geriatric Patients – Therapy in these age groups should be initiated with Tofranil™, brand of imipramine hydrochloride tablets, at a total daily dosage of 25 to 50 mg, since Tofranil-PM capsules are not available in these strengths. Dosage may be increased according to response and tolerance, but it is generally unnecessary to exceed 100 mg/day in these patients. Tofranil-PM capsules may be used when total daily dosage is established at 75 mg or higher. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Adolescent and geriatric patients can usually be maintained at lower dosage. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased. The total daily maintenance dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Tofranil-PM. Conversely, at least 14 days should be allowed after stopping Tofranil-PM before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of Tofranil-PM With Other MAOIs, Such as Linezolid or Methylene Blue Do not start Tofranil-PM in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). Page 14 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In some cases, a patient already receiving Tofranil-PM therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Tofranil-PM should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Tofranil-PM may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Tofranil-PM is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). HOW SUPPLIED Tofranil-PM™ (imipramine pamoate) capsules Capsules 75 mg – coral body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 75 mg”. Bottles of 30 …………….NDC 0406-9923-03 Capsules 100 mg – maize body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 100 mg”. Bottles of 30……….…….NDC 0406-9924-03 Capsules 125 mg – ivory body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 125 mg”. Bottles of 30……….…….NDC 0406-9925-03 Capsules 150 mg – coral body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 150 mg”. Bottles of 30………..…….NDC 0406-9926-03 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in tight container (USP) with a child-resistant closure. ANIMAL PHARMACOLOGY & TOXICOLOGY A. Acute: Oral LD50: Mouse 2185 mg/kg Rat (F) 1142 mg/kg (M) 1807 mg/kg Rabbit 1016 mg/kg Dog 693 mg/kg (Emesis ED50) Page 15 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda B. Subacute: Two three-month studies in dogs gave evidence of an adverse drug effect on the testes, but only at the highest dose level employed, i.e., 90 mg/kg (10 times the maximum human dose). Depending on the histological section of the testes examined, the findings consisted of a range of degenerative changes up to and including complete atrophy of the seminiferous tubules, with spermatogenesis usually arrested. Human studies show no definitive effect on sperm count, sperm motility, sperm morphology or volume of ejaculate. Rat One three-month study was done in rats at dosage levels comparable to those of the dog studies. No adverse drug effect on the testes was noted in this study, as confirmed by histological examination. C. Reproduction/Teratogenic: Oral: Imipramine pamoate was fed to male and female albino rats for 28 weeks through two breeding cycles at dose levels of 15 mg/kg/day and 40 mg/kg/day (equivalent to 2 1/2 and 7 times the maximum human dose). No abnormalities which could be related to drug administration were noted in gross inspection. Autopsies performed on pups from the second breeding likewise revealed no pathological changes in organs or tissues; however, a decrease in mean litter size from both matings was noted in the drug-treated groups and significant growth suppression occurred in the nursing pups of both sexes in the high group as well as in the females of the low-level group. Finally, the lactation index (pups weaned divided by number left to nurse) was significantly lower in the second litter of the high-level group. Tofranil and Tofranil-PM are trademarks of Mallinckrodt LLC. M is a trademark of Mallinckrodt LLC. Manufactured by Patheon Inc. Whitby, Ontario, Canada L1N 5Z5 Manufactured for Mallinckrodt Inc. Hazelwood, MO 63042 USA Page 16 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide - Tofranil-PM™ (imipramine pamoate) capsules Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety Page 17 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood Visual problems • eye pain • changes in vision • swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Who should not take Tofranil-PM? Do not take Tofranil-PM if you: • take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. o Do not take an MAOI within 2 weeks of stopping Tofranil-PM unless directed to do so by your physician. o Do not start Tofranil-PM if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show Page 18 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. This Medication Guide has been approved by the U.S. Food and Drug Administration. Tofranil-PM is a trademark of Mallinckrodt LLC. Manufactured by Patheon Inc. Whitby, Ontario, Canada L1N 5Z5 Manufactured for Mallinckrodt Inc. Hazelwood, MO 63042 USA Rev 05/2014 company logo Page 19 of 19 Reference ID: 3540545 052014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:08.631289	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/017090s077lbl.pdf', 'application_number': 17090, 'submission_type': 'SUPPL ', 'submission_number': 77}
10,967	Tofranil-PM™ (imipramine pamoate) capsules (75 mg, 100 mg, 125 mg and 150 mg) For oral administration Rx only Prescribing Information Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of imipramine pamoate or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Imipramine pamoate is not approved for use in pediatric patients (see WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use). DESCRIPTION Tofranil-PM™ (imipramine pamoate) capsules are a tricyclic antidepressant, available as capsules for oral administration. The 75-, 100-, 125-, and 150-mg capsules contain imipramine pamoate equivalent to 75, 100, 125, and 150 mg of imipramine hydrochloride. Imipramine pamoate is 5-[3-(dimethylamino)propyl]-10,11-dihydro-5H dibenz[b,f]azepine 4, 4'-methylenebis-(3-hydroxy-2-naphthoate) (2:1), and its structural formula is structural formula (C19H24N2)2●C23H16O6 M.W. = 949.21 Page 1 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Imipramine pamoate is a fine, yellow, tasteless, odorless powder. It is soluble in ethanol, in acetone, in ether, in chloroform, and in carbon tetrachloride, and is insoluble in water. Inactive Ingredients. D&C Red No. 28, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 (100 mg and 125 mg capsules only), gelatin, magnesium stearate, parabens, starch, talc, and titanium dioxide. CLINICAL PHARMACOLOGY The mechanism of action of imipramine is not definitely known. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings. INDICATIONS AND USAGE For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident. CONTRAINDICATIONS Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with Tofranil-PM or within 14 days of stopping treatment with Tofranil-PM is contraindicated because of an increased risk of serotonin syndrome. The use of Tofranil-PM within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). Starting Tofranil-PM in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION). Myocardial Infarction The drug is contraindicated during the acute recovery period after a myocardial infarction. Hypersensitivity to Tricyclic Antidepressants Patients with a known hypersensitivity to this compound should not be given the drug. The possibility of cross-sensitivity to other dibenzazepine compounds should be kept in mind. Page 2 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long- standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 18-24 14 additional cases 5 additional cases Decreases Compared to Placebo 25-64 ≥65 1 fewer case 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. Page 3 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for imipramine pamoate should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder – A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should Page 4 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be noted that imipramine pamoate is not approved for use in treating bipolar depression. Extreme caution should be used when this drug is given to patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes, and tachycardia. These patients require cardiac surveillance at all dosage levels of the drug; patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold; patients receiving guanethidine, clonidine, or similar agents, since imipramine pamoate may block the pharmacologic effects of these drugs; patients receiving methylphenidate hydrochloride. Since methylphenidate hydrochloride may inhibit the metabolism of imipramine pamoate, downward dosage adjustment of imipramine pamoate may be required when given concomitantly with methylphenidate hydrochloride. Since imipramine pamoate may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly. Tofranil-PM may enhance the CNS depressant effects of alcohol. Therefore, it should be borne in mind that the dangers inherent in a suicide attempt or accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol (see PRECAUTIONS). Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Tofranil-PM, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of Tofranil-PM with MAOIs intended to treat psychiatric disorders is contraindicated. Tofranil-PM should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved Page 5 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Tofranil-PM. Tofranil-PM should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of Tofranil-PM with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Tofranil-PM and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Tofranil-PM may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. PRECAUTIONS General An ECG recording should be taken prior to the initiation of larger-than-usual doses of imipramine pamoate and at appropriate intervals thereafter until steady state is achieved. (Patients with any evidence of cardiovascular disease require cardiac surveillance at all dosage levels of the drug. See WARNINGS.) Elderly patients and patients with cardiac disease or a prior history of cardiac disease are at special risk of developing the cardiac abnormalities associated with the use of imipramine pamoate. It should be kept in mind that the possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Such patients should be carefully supervised during the early phase of treatment with imipramine pamoate and may require hospitalization. Prescriptions should be written for the smallest amount feasible. Hypomanic or manic episodes may occur, particularly in patients with cyclic disorders. Such reactions may necessitate discontinuation of the drug. If needed, imipramine pamoate may be resumed in lower dosage when these episodes are relieved. Administration of a tranquilizer may be useful in controlling such episodes. An activation of the psychosis may occasionally be observed in schizophrenic patients and may require reduction of dosage and the addition of a phenothiazine. Page 6 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concurrent administration of imipramine pamoate with electroshock therapy may increase the hazards: such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience. Patients taking imipramine pamoate should avoid excessive exposure to sunlight since there have been reports of photosensitization. Both elevation and lowering of blood sugar levels have been reported with imipramine pamoate use. Imipramine pamoate should be used with caution in patients with significantly impaired renal or hepatic function. Patients who develop a fever and a sore throat during therapy with imipramine pamoate should have leukocyte and differential blood counts performed. Imipramine pamoate should be discontinued if there is evidence of pathological neutrophil depression. Prior to elective surgery, imipramine pamoate should be discontinued for as long as the clinical situation will allow. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with imipramine pamoate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for imipramine pamoate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking imipramine pamoate. Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of Page 7 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be advised that taking Tofranil-PM can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Drug Interactions Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Page 8 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary. In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents) in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus). Close supervision and careful adjustment of dosage is required when imipramine pamoate is administered concomitantly with anticholinergic drugs. Avoid the use of preparations, such as decongestants and local anesthetics, that contain any sympathomimetic amine (e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Caution should be exercised when imipramine pamoate is used with agents that lower blood pressure. Imipramine pamoate may potentiate the effects of CNS depressant drugs. Patients should be warned that imipramine pamoate may enhance the CNS depressant effects of alcohol (see WARNINGS). Monoamine Oxidase Inhibitors (MAOIs) (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Serotonergic Drugs (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Pregnancy Animal reproduction studies have yielded inconclusive results (see also ANIMAL PHARMACOLOGY & TOXICOLOGY). There have been no well-controlled studies conducted with pregnant women to determine the effect of imipramine on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of imipramine cannot be excluded. Therefore, imipramine should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus. Nursing Mothers Limited data suggest that imipramine is likely to be excreted in human breast milk. As a general rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child. Page 9 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). It is generally recommended that Tofranil-PM should not be used in children because of the increased potential for acute overdosage due to the high unit potency (75 mg, 100 mg, 125 mg, and 150 mg). Each capsule contains imipramine pamoate equivalent to 75 mg, 100 mg, 125 mg, or 150 mg imipramine hydrochloride. Anyone considering the use of imipramine pamoate in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with Tofranil™ , brand of imipramine hydrochloride tablets, in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There were no additional adverse experiences identified in the elderly. Clinical studies of Tofranil™, brand of imipramine hydrochloride tablets, in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See also DOSAGE AND ADMINISTRATION, Adolescent and Geriatric Patients) (See also PRECAUTIONS, General) ADVERSE REACTIONS Note: Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when imipramine is administered. Cardiovascular: Orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke. Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis. Page 10 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Neurological: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus. Anticholinergic: Dry mouth, and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. Allergic: Skin rash, petechiae, urticaria, itching, photosensitization; edema (general or of face and tongue); drug fever; cross-sensitivity with desipramine. Hematologic: Bone marrow depression including agranulocytosis; eosinophilia; purpura; thrombocytopenia. Gastrointestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue. Endocrine: Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; inappropriate antidiuretic hormone (ADH) secretion syndrome. Other: Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling. Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache and malaise. Postmarketing Experience The following adverse drug reaction has been reported during post-approval use of Tofranil-PM. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency. Eye disorders: angle-closure glaucoma OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible. Page 11 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Children have been reported to be more sensitive than adults to an acute overdosage of imipramine pamoate. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal. Manifestations These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements. Cardiac abnormalities may include tachycardia, and signs of congestive failure. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present. Management Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination – All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular – A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). Page 12 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning. CNS – In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management – The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. DOSAGE AND ADMINISTRATION The following recommended dosages for Tofranil-PM should be modified as necessary by the clinical response and any evidence of intolerance. Initial Adult Dosage Outpatients – Therapy should be initiated at 75 mg/day. Dosage may be increased to 150 mg/day which is the dose level at which optimum response is usually obtained. If necessary, dosage may be increased to 200 mg/day. Dosage higher than 75 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Hospitalized Patients – Therapy should be initiated at 100 to 150 mg/day and may be increased to 200 mg/day. If there is no response after two weeks, dosage should be increased to 250 to 300 mg/day. Dosage higher than 150 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be Page 13 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda given at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Adult Maintenance Dosage – Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased. The usual maintenance dosage is 75 to 150 mg/day. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted. Adolescent and Geriatric Patients – Therapy in these age groups should be initiated with Tofranil™, brand of imipramine hydrochloride tablets, at a total daily dosage of 25 to 50 mg, since Tofranil-PM capsules are not available in these strengths. Dosage may be increased according to response and tolerance, but it is generally unnecessary to exceed 100 mg/day in these patients. Tofranil-PM capsules may be used when total daily dosage is established at 75 mg or higher. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Adolescent and geriatric patients can usually be maintained at lower dosage. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased. The total daily maintenance dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Tofranil-PM. Conversely, at least Page 14 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 days should be allowed after stopping Tofranil-PM before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of Tofranil-PM With Other MAOIs, Such as Linezolid or Methylene Blue Do not start Tofranil-PM in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). In some cases, a patient already receiving Tofranil-PM therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Tofranil-PM should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Tofranil-PM may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Tofranil-PM is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). HOW SUPPLIED Tofranil-PM™ (imipramine pamoate) capsules Capsules 75 mg – coral body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 75 mg”. Bottles of 30 …………….NDC 0406-9923-03 Capsules 100 mg – maize body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 100 mg”. Bottles of 30……….…….NDC 0406-9924-03 Capsules 125 mg – ivory body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 125 mg”. Bottles of 30……….…….NDC 0406-9925-03 Capsules 150 mg – coral body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 150 mg”. Bottles of 30………..…….NDC 0406-9926-03 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in tight container (USP) with a child-resistant closure. Page 15 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ANIMAL PHARMACOLOGY & TOXICOLOGY A. Acute: Oral LD50: Mouse 2185 mg/kg Rat (F) 1142 mg/kg (M) 1807 mg/kg Rabbit 1016 mg/kg Dog 693 mg/kg (Emesis ED50) B. Subacute: Two three-month studies in dogs gave evidence of an adverse drug effect on the testes, but only at the highest dose level employed, i.e., 90 mg/kg (10 times the maximum human dose). Depending on the histological section of the testes examined, the findings consisted of a range of degenerative changes up to and including complete atrophy of the seminiferous tubules, with spermatogenesis usually arrested. Human studies show no definitive effect on sperm count, sperm motility, sperm morphology or volume of ejaculate. Rat One three-month study was done in rats at dosage levels comparable to those of the dog studies. No adverse drug effect on the testes was noted in this study, as confirmed by histological examination. C. Reproduction/Teratogenic: Oral: Imipramine pamoate was fed to male and female albino rats for 28 weeks through two breeding cycles at dose levels of 15 mg/kg/day and 40 mg/kg/day (equivalent to 2 1/2 and 7 times the maximum human dose). No abnormalities which could be related to drug administration were noted in gross inspection. Autopsies performed on pups from the second breeding likewise revealed no pathological changes in organs or tissues; however, a decrease in mean litter size from both matings was noted in the drug-treated groups and significant growth suppression occurred in the nursing pups of both sexes in the high group as well as in the females of the low-level group. Finally, the lactation index (pups weaned divided by number left to nurse) was significantly lower in the second litter of the high-level group. Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo, M and other brands are trademarks of a Mallinckrodt company. © 2014 Mallinckrodt. Page 16 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Manufactured by Patheon Inc. Whitby, Ontario, Canada L1N 5Z5 Manufactured for Mallinckrodt Inc. Hazelwood, MO 63042 USA Page 17 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide - Tofranil-PM™ (imipramine pamoate) capsules Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:  all risks and benefits of treatment with antidepressant medicines  all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?  Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.  Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.  Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:  thoughts about suicide or dying  attempts to commit suicide  new or worse depression  new or worse anxiety Page 18 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  feeling very agitated or restless  panic attacks  trouble sleeping (insomnia)  new or worse irritability  acting aggressive, being angry, or violent  acting on dangerous impulses  an extreme increase in activity and talking (mania)  other unusual changes in behavior or mood Visual problems  eye pain  changes in vision  swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Who should not take Tofranil-PM? Do not take Tofranil-PM if you:  take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. o Do not take an MAOI within 2 weeks of stopping Tofranil-PM unless directed to do so by your physician. o Do not start Tofranil-PM if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. What else do I need to know about antidepressant medicines?  Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.  Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.  Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.  Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show Page 19 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the healthcare provider. Do not start new medicines without first checking with your healthcare provider.  Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. This Medication Guide has been approved by the U.S. Food and Drug Administration. Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo, and other brands are trademarks of a Mallinckrodt company. © 2014 Mallinckrodt. Manufactured by Patheon Inc. Whitby, Ontario, Canada L1N 5Z5 Manufactured for Mallinckrodt Inc. Hazelwood, MO 63042 USA Rev 06/2014 company logo Page 20 of 20 Reference ID: 3600048 062014-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:08.665772	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/017090s078lbl.pdf', 'application_number': 17090, 'submission_type': 'SUPPL ', 'submission_number': 78}
10,965	s t r uctural formula Tofranil-PM™ (imipramine pamoate) capsules (75 mg, 100 mg, 125 mg and 150 mg) For oral administration Rx only Prescribing Information Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of imipramine pamoate or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Imipramine pamoate is not approved for use in pediatric patients (see WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use). DESCRIPTION Tofranil-PM™ (imipramine pamoate) capsules are a tricyclic antidepressant, available as capsules for oral administration. The 75-, 100-, 125-, and 150-mg capsules contain imipramine pamoate equivalent to 75, 100, 125, and 150 mg of imipramine hydrochloride. Imipramine pamoate is 5-[3-(dimethylamino)propyl]-10,11-dihydro-5H dibenz[b,f]azepine 4, 4'-methylenebis-(3-hydroxy-2-naphthoate) (2:1), and its structural formula is Page 1 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Imipramine pamoate is a fine, yellow, tasteless, odorless powder. It is soluble in ethanol, in acetone, in ether, in chloroform, and in carbon tetrachloride, and is insoluble in water. Inactive Ingredients. D&C Red No. 28, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 (100 mg and 125 mg capsules only), gelatin, magnesium stearate, parabens, starch, talc, and titanium dioxide. CLINICAL PHARMACOLOGY The mechanism of action of imipramine is not definitely known. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings. INDICATIONS AND USAGE For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident. CONTRAINDICATIONS Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with Tofranil-PM or within 14 days of stopping treatment with Tofranil-PM is contraindicated because of an increased risk of serotonin syndrome. The use of Tofranil-PM within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). Starting Tofranil-PM in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION). Myocardial Infarction The drug is contraindicated during the acute recovery period after a myocardial infarction. Hypersensitivity to Tricyclic Antidepressants Patients with a known hypersensitivity to this compound should not be given the drug. The possibility of cross-sensitivity to other dibenzazepine compounds should be kept in mind. Page 2 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long- standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 18-24 14 additional cases 5 additional cases Decreases Compared to Placebo 25-64 ≥65 1 fewer case 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. Page 3 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for imipramine pamoate should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder – A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should Page 4 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be noted that imipramine pamoate is not approved for use in treating bipolar depression. Extreme caution should be used when this drug is given to patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes, and tachycardia. These patients require cardiac surveillance at all dosage levels of the drug; patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold; patients receiving guanethidine, clonidine, or similar agents, since imipramine pamoate may block the pharmacologic effects of these drugs; patients receiving methylphenidate hydrochloride. Since methylphenidate hydrochloride may inhibit the metabolism of imipramine pamoate, downward dosage adjustment of imipramine pamoate may be required when given concomitantly with methylphenidate hydrochloride. Since imipramine pamoate may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly. Tofranil-PM may enhance the CNS depressant effects of alcohol. Therefore, it should be borne in mind that the dangers inherent in a suicide attempt or accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol (see PRECAUTIONS). Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Tofranil-PM, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of Tofranil-PM with MAOIs intended to treat psychiatric disorders is contraindicated. Tofranil-PM should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved Page 5 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Tofranil-PM. Tofranil-PM should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of Tofranil-PM with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Tofranil-PM and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. PRECAUTIONS General An ECG recording should be taken prior to the initiation of larger-than-usual doses of imipramine pamoate and at appropriate intervals thereafter until steady state is achieved. (Patients with any evidence of cardiovascular disease require cardiac surveillance at all dosage levels of the drug. See WARNINGS.) Elderly patients and patients with cardiac disease or a prior history of cardiac disease are at special risk of developing the cardiac abnormalities associated with the use of imipramine pamoate. It should be kept in mind that the possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Such patients should be carefully supervised during the early phase of treatment with imipramine pamoate and may require hospitalization. Prescriptions should be written for the smallest amount feasible. Hypomanic or manic episodes may occur, particularly in patients with cyclic disorders. Such reactions may necessitate discontinuation of the drug. If needed, imipramine pamoate may be resumed in lower dosage when these episodes are relieved. Administration of a tranquilizer may be useful in controlling such episodes. An activation of the psychosis may occasionally be observed in schizophrenic patients and may require reduction of dosage and the addition of a phenothiazine. Concurrent administration of imipramine pamoate with electroshock therapy may increase the hazards: such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience. Patients taking imipramine pamoate should avoid excessive exposure to sunlight since there have been reports of photosensitization. Page 6 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Both elevation and lowering of blood sugar levels have been reported with imipramine pamoate use. Imipramine pamoate should be used with caution in patients with significantly impaired renal or hepatic function. Patients who develop a fever and a sore throat during therapy with imipramine pamoate should have leukocyte and differential blood counts performed. Imipramine pamoate should be discontinued if there is evidence of pathological neutrophil depression. Prior to elective surgery, imipramine pamoate should be discontinued for as long as the clinical situation will allow. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with imipramine pamoate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for imipramine pamoate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking imipramine pamoate. Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Drug Interactions Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Page 7 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Caucasian population (about 7% to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary. In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents) in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus). Close supervision and careful adjustment of dosage is required when imipramine pamoate is administered concomitantly with anticholinergic drugs. Avoid the use of preparations, such as decongestants and local anesthetics, that contain any sympathomimetic amine (e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Page 8 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Caution should be exercised when imipramine pamoate is used with agents that lower blood pressure. Imipramine pamoate may potentiate the effects of CNS depressant drugs. Patients should be warned that imipramine pamoate may enhance the CNS depressant effects of alcohol (see WARNINGS). Monoamine Oxidase Inhibitors (MAOIs) (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Serotonergic Drugs (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Pregnancy Animal reproduction studies have yielded inconclusive results (see also ANIMAL PHARMACOLOGY & TOXICOLOGY). There have been no well-controlled studies conducted with pregnant women to determine the effect of imipramine on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of imipramine cannot be excluded. Therefore, imipramine should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus. Nursing Mothers Limited data suggest that imipramine is likely to be excreted in human breast milk. As a general rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). It is generally recommended that Tofranil-PM should not be used in children because of the increased potential for acute overdosage due to the high unit potency (75 mg, 100 mg, 125 mg, and 150 mg). Each capsule contains imipramine pamoate equivalent to 75 mg, 100 mg, 125 mg, or 150 mg imipramine hydrochloride. Anyone considering the use of imipramine pamoate in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with Tofranil™, brand of imipramine Page 9 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hydrochloride tablets, in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There were no additional adverse experiences identified in the elderly. Clinical studies of Tofranil™, brand of imipramine hydrochloride tablets, in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (see also DOSAGE AND ADMINISTRATION in Adolescent and Geriatric Patients) (see also PRECAUTIONS, General) ADVERSE REACTIONS Note: Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when imipramine is administered. Cardiovascular: Orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke. Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis. Neurological: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus. Anticholinergic: Dry mouth, and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. Allergic: Skin rash, petechiae, urticaria, itching, photosensitization; edema (general or of face and tongue); drug fever; cross-sensitivity with desipramine. Hematologic: Bone marrow depression including agranulocytosis; eosinophilia; purpura; thrombocytopenia. Page 10 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue. Endocrine: Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; inappropriate antidiuretic hormone (ADH) secretion syndrome. Other: Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling. Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache and malaise. OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible. Children have been reported to be more sensitive than adults to an acute overdosage of imipramine pamoate. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal. Manifestations These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements. Cardiac abnormalities may include tachycardia, and signs of congestive failure. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present. Management Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination. A minimum of Page 11 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination – All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular – A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning. CNS – In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management – The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. Page 12 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION The following recommended dosages for Tofranil-PM should be modified as necessary by the clinical response and any evidence of intolerance. Initial Adult Dosage Outpatients – Therapy should be initiated at 75 mg/day. Dosage may be increased to 150 mg/day which is the dose level at which optimum response is usually obtained. If necessary, dosage may be increased to 200 mg/day. Dosage higher than 75 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Hospitalized Patients – Therapy should be initiated at 100 to 150 mg/day and may be increased to 200 mg/day. If there is no response after two weeks, dosage should be increased to 250 to 300 mg/day. Dosage higher than 150 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Adult Maintenance Dosage – Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased. The usual maintenance dosage is 75 to 150 mg/day. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted. Adolescent and Geriatric Patients – Therapy in these age groups should be initiated with Tofranil™, brand of imipramine hydrochloride tablets, at a total daily dosage of 25 to 50 mg, since Tofranil-PM capsules are not available in these strengths. Dosage may be increased according to response and tolerance, but it is generally unnecessary to Page 13 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda exceed 100 mg/day in these patients. Tofranil-PM capsules may be used when total daily dosage is established at 75 mg or higher. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients. Adolescent and geriatric patients can usually be maintained at lower dosage. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased. The total daily maintenance dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule. In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Tofranil-PM. Conversely, at least 14 days should be allowed after stopping Tofranil-PM before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of Tofranil-PM With Other MAOIs, Such as Linezolid or Methylene Blue Do not start Tofranil-PM in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). In some cases, a patient already receiving Tofranil-PM therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Tofranil-PM should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Tofranil-PM may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral Page 14 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Tofranil-PM is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). HOW SUPPLIED Tofranil-PM™ (imipramine pamoate) capsules Capsules 75 mg – coral body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 75 mg”. Bottles of 30 …………….NDC 0406-9923-03 Capsules 100 mg – maize body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 100 mg”. Bottles of 30……….…….NDC 0406-9924-03 Capsules 125 mg – ivory body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 125 mg”. Bottles of 30……….…….NDC 0406-9925-03 Capsules 150 mg – coral body imprinted in black “M” and coral cap imprinted in black “Tofranil-PM 150 mg”. Bottles of 30………..…….NDC 0406-9926-03 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in tight container (USP) with a child-resistant closure. ANIMAL PHARMACOLOGY & TOXICOLOGY A. Acute: Oral LD50: Mouse 2185 mg/kg Rat (F) 1142 mg/kg (M) 1807 mg/kg Rabbit 1016 mg/kg Dog 693 mg/kg (Emesis ED50) B. Subacute: Two three-month studies in dogs gave evidence of an adverse drug effect on the testes, but only at the highest dose level employed, i.e., 90 mg/kg (10 times the maximum human dose). Depending on the histological section of the testes examined, the findings consisted of a range of degenerative changes up to and including complete atrophy of the seminiferous tubules, with spermatogenesis usually arrested. Human studies show no definitive effect on sperm count, sperm motility, sperm morphology or volume of ejaculate. Page 15 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rat One three-month study was done in rats at dosage levels comparable to those of the dog studies. No adverse drug effect on the testes was noted in this study, as confirmed by histological examination. C. Reproduction/Teratogenic: Oral: Imipramine pamoate was fed to male and female albino rats for 28 weeks through two breeding cycles at dose levels of 15 mg/kg/day and 40 mg/kg/day (equivalent to 2 1/2 and 7 times the maximum human dose). No abnormalities which could be related to drug administration were noted in gross inspection. Autopsies performed on pups from the second breeding likewise revealed no pathological changes in organs or tissues; however, a decrease in mean litter size from both matings was noted in the drug-treated groups and significant growth suppression occurred in the nursing pups of both sexes in the high group as well as in the females of the low-level group. Finally, the lactation index (pups weaned divided by number left to nurse) was significantly lower in the second litter of the high-level group. Tofranil and Tofranil-PM are trademarks of Mallinckrodt LLC. M is a trademark of Mallinckrodt LLC. Manufactured by Patheon Inc. Whitby, Ontario, Canada L1N 5Z5 Manufactured for Mallinckrodt Inc. Hazelwood, MO 63042 USA Medication Guide - Tofranil-PM™ (imipramine pamoate) capsules Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:  all risks and benefits of treatment with antidepressant medicines  all treatment choices for depression or other serious mental illness Page 16 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?  Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.  Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.  Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:  thoughts about suicide or dying  attempts to commit suicide  new or worse depression  new or worse anxiety  feeling very agitated or restless  panic attacks  trouble sleeping (insomnia)  new or worse irritability  acting aggressive, being angry, or violent  acting on dangerous impulses  an extreme increase in activity and talking (mania)  other unusual changes in behavior or mood Who should not take Tofranil-PM? Do not take Tofranil-PM if you: Page 17 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. o Do not take an MAOI within 2 weeks of stopping Tofranil-PM unless directed to do so by your physician. o Do not start Tofranil-PM if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. What else do I need to know about antidepressant medicines?  Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.  Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.  Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.  Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.  Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. This Medication Guide has been approved by the U.S. Food and Drug Administration. Tofranil-PM is a trademark of Mallinckrodt LLC. Manufactured by Patheon Inc. Whitby, Ontario, Canada L1N 5Z5 Manufactured for Mallinckrodt Inc. Page 18 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hazelwood, MO 63042 USA Rev 10/2012 company logo Page 19 of 19 10_2012.2 Reference ID: 3209061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:08.730786	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017090s076lbl.pdf', 'application_number': 17090, 'submission_type': 'SUPPL ', 'submission_number': 76}
10,968	TRANXENE* T-TAB® Tablets clorazepate dipotassium tablets, USP Rx only DESCRIPTION Chemically, TRANXENE is a benzodiazepine. The empirical formula is C16H11ClK2N2O4; the molecular weight is 408.92; 1H-1, 4-Benzodiazepine-3-carboxylic acid, 7-chloro-2,3 dihydro-2-oxo-5-phenyl-, potassium salt compound with potassium hydroxide (1:1) and the Chemical Structure The compound occurs as a fine, light yellow, practically odorless powder. It is insoluble in the common organic solvents, but very soluble in water. Aqueous solutions are unstable, clear, light yellow, and alkaline. TRANXENE T-TAB tablets contain either 3.75 mg, 7.5 mg or 15 mg of clorazepate dipotassium for oral administration. Inactive ingredients for TRANXENE T-TAB Tablets: Colloidal silicon dioxide, FD&C Blue No. 2 (3.75 mg only), FD&C Yellow No. 6 (7.5 mg only), FD&C Red No. 3 (15 mg only), magnesium oxide, magnesium stearate, microcrystalline cellulose, potassium carbonate, potassium chloride, and talc. CLINICAL PHARMACOLOGY Pharmacologically, clorazepate dipotassium has the characteristics of the benzodiazepines. It has depressant effects on the central nervous system. The primary metabolite, nordiazepam, quickly appears in the blood stream. The serum half-life is about 2 days. The drug is metabolized in the liver and excreted primarily in the urine. Studies in healthy men have shown that clorazepate dipotassium has depressant effects on the central nervous system. Prolonged administration of single daily doses as high as 120 mg was without toxic effects. Abrupt cessation of high doses was followed in some patients by nervousness, insomnia, irritability, diarrhea, muscle aches, or memory impairment. Since orally administered clorazepate dipotassium is rapidly decarboxylated to form nordiazepam, there is essentially no circulating parent drug. Nordiazepam, the primary metabolite, quickly appears in the blood and is eliminated from the plasma with an apparent half-life of about 40 to 50 hours. Plasma levels of nordiazepam increase proportionally with TRANXENE dose and show moderate accumulation with repeated administration. The protein binding of nordiazepam in plasma is high (97-98%). Within 10 days after oral administration of a 15 mg (50µCi) dose of 14C-TRANXENE to two This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda volunteers, 62-67% of the radioactivity was excreted in the urine and 15-19% was eliminated in the feces. Both subjects were still excreting measurable amounts of radioactivity in the urine (about l% of the 14C-dose) on day ten. Nordiazepam is further metabolized by hydroxylation. The major urinary metabolite is conjugated oxazepam (3-hydroxynordiazepam), and smaller amounts of conjugated p hydroxynordiazepam and nordiazepam are also found in the urine. INDICATIONS AND USAGE TRANXENE is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. TRANXENE tablets are indicated as adjunctive therapy in the management of partial seizures. The effectiveness of TRANXENE tablets in long-term management of anxiety, that is, more than 4 months, has not been assessed by systematic clinical studies. Long-term studies in epileptic patients, however, have shown continued therapeutic activity. The physician should reassess periodically the usefulness of the drug for the individual patient. TRANXENE tablets are indicated for the symptomatic relief of acute alcohol withdrawal. CONTRAINDICATIONS TRANXENE tablets are contraindicated in patients with a known hypersensitivity to the drug and in those with acute narrow angle glaucoma. WARNINGS Use in Depressive Neuroses or Psychotic Reactions: TRANXENE tablets are not recommended for use in depressive neuroses or in psychotic reactions. Use in Children: Because of the lack of sufficient clinical experience, TRANXENE tablets are not recommended for use in patients less than 9 years of age. Interference with Psychomotor Performance: Patients taking TRANXENE tablets should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating dangerous machinery including motor vehicles. Concomitant Use with CNS Depressants: Since TRANXENE has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS depressant drugs, and cautioned that the effects of alcohol may be increased. Physical and Psychological Dependence: Withdrawal symptoms (similar in character to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda those noted with barbiturates and alcohol) have occurred following abrupt discontinuance of clorazepate. Withdrawal symptoms associated with the abrupt discontinuation of benzodiazepines have included convulsions, delirium, tremor, abdominal and muscle cramps, vomiting, sweating, nervousness, insomnia, irritability, diarrhea, and memory impairment. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation of clorazepate should generally be avoided and a gradual dosage tapering schedule followed. Caution should be observed in patients who are considered to have a psychological potential for drug dependence. Evidence of drug dependence has been observed in dogs and rabbits which was characterized by convulsive seizures when the drug was abruptly withdrawn or the dose was reduced; the syndrome in dogs could be abolished by administration of clorazepate. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including TRANXENE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table1: Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Relative Risk: Risk Difference: with Events Per Patients Incidence of Additional Drug 1000 Patients with Events Events in Drug Patients with Per 1000 Patients/Incidence Events Per 1000 Patients in Placebo Patients Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing TRANXENE or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self- harm. Behaviors of concern should be reported immediately to healthcare providers. Usage in Pregnancy: An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Clorazepate dipotassium, a benzodiazepine derivative, has not been studied adequately to determine whether it, too, may be associated with an increased risk of fetal abnormality. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug. To provide information regarding the effects of in utero exposure to TRANXENE, physicians are advised to recommend that pregnant patients taking TRANXENE enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Usage during Lactation: TRANXENE tablets should not be given to nursing mothers since it has been reported that nordiazepam is excreted in human breast milk. PRECAUTIONS In those patients in which a degree of depression accompanies the anxiety, suicidal tendencies may be present and protective measures may be required. The least amount of drug that is feasible should be available to the patient. Patients taking TRANXENE tablets for prolonged periods should have blood counts and liver function tests periodically. The usual precautions in treating patients with impaired renal or hepatic function should also be observed. In elderly or debilitated patients, the initial dose should be small, and increments should be made gradually, in accordance with the response of the patient, to preclude ataxia or excessive sedation. Information for Patients: To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is essential that they consult with their physician before either increasing the dose or abruptly discontinuing this drug. Patients, their caregivers, and families should be counseled that AEDs, including TRANXENE, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 (see Usage in Pregnancy). Pediatric Use: See WARNINGS. Geriatric Use: Clinical studies of TRANXENE were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects. Elderly or debilitated patients may be especially sensitive to the effects of all benzodiazepines, including TRANXENE. In general, elderly or debilitated patients should be started on lower doses of TRANXENE and observed closely, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy. Dose adjustments This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda should also be made slowly, and with more caution in this patient population (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS The side effect most frequently reported was drowsiness. Less commonly reported (in descending order of occurrence) were: dizziness, various gastrointestinal complaints, nervousness, blurred vision, dry mouth, headache, and mental confusion. Other side effects included insomnia, transient skin rashes, fatigue, ataxia, genitourinary complaints, irritability, diplopia, depression, tremor, and slurred speech. There have been reports of abnormal liver and kidney function tests and of decrease in hematocrit. Decrease in systolic blood pressure has been observed. DOSAGE AND ADMINISTRATION For the symptomatic relief of anxiety: TRANXENE T-TAB tablets are administered orally in divided doses. The usual daily dose is 30 mg. The dose should be adjusted gradually within the range of 15 to 60 mg daily in accordance with the response of the patient. In elderly or debilitated patients it is advisable to initiate treatment at a daily dose of 7.5 to 15 mg. TRANXENE tablets may also be administered in a single dose daily at bedtime; the recommended initial dose is 15 mg. After the initial dose, the response of the patient may require adjustment of subsequent dosage. Lower doses may be indicated in the elderly patient. Drowsiness may occur at the initiation of treatment and with dosage increment. For the symptomatic relief of acute alcohol withdrawal: The following dosage schedule is recommended: 1st 24 hours followed by (Day 1) doses 30 mg initially; 30 to 60 mg in divided 2nd 24 hours doses (Day 2) 45 to 90 mg in divided 3rd 24 hours divided doses (Day 3) 22.5 to 45 mg in Day 4 doses 15 to 30 mg in divided Thereafter, gradually reduce the daily dose to 7.5 to 15 mg. Discontinue drug therapy as soon This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda as patient’s condition is stable. The maximum recommended total daily dose is 90 mg. Avoid excessive reductions in the total amount of drug administered on successive days. As an Adjunct to Antiepileptic Drugs: In order to minimize drowsiness, the recommended initial dosages and dosage increments should not be exceeded. Adults: The maximum recommended initial dose in patients over 12 years old is 7.5 mg three times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 90 mg/day. Children (9-12 years): The maximum recommended initial dose is 7.5 mg two times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 60 mg/day. DRUG INTERACTIONS If TRANXENE is to be combined with other drugs acting on the central nervous system, careful consideration should be given to the pharmacology of the agents to be employed. Animal experience indicates that clorazepate dipotassium prolongs the sleeping time after hexobarbital or after ethyl alcohol, increases the inhibitory effects of chlorpromazine, but does not exhibit monoamine oxidase inhibition. Clinical studies have shown increased sedation with concurrent hypnotic medications. The actions of the benzodiazepines may be potentiated by barbiturates, narcotics, phenothiazines, monoamine oxidase inhibitors or other antidepressants. If TRANXENE tablets are used to treat anxiety associated with somatic disease states, careful attention must be paid to possible drug interaction with concomitant medication. In bioavailability studies with normal subjects, the concurrent administration of antacids at therapeutic levels did not significantly influence the bioavailability of TRANXENE tablets. OVERDOSAGE Overdosage is usually manifested by varying degrees of CNS depression ranging from slight sedation to coma. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. The treatment of overdosage should consist of the general measures employed in the management of overdosage of any CNS depressant. Gastric evacuation either by the induction of emesis, lavage, or both, should be performed immediately. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. Hypotension, though rarely reported, may occur with large overdoses. In such cases the use of agents such as norepinephrine bitartrate injection, USP or metaraminol bitartrate injection, USP should be considered. While reports indicate that individuals have survived overdoses of clorazepate dipotassium as This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda high as 450 to 675 mg, these doses are not necessarily an accurate indication of the amount of drug absorbed since the time interval between ingestion and the institution of treatment was not always known. Sedation in varying degrees was the most common physiological manifestation of clorazepate dipotassium overdosage. Deep coma when it occurred was usually associated with the ingestion of other drugs in addition to clorazepate dipotassium. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use. ANIMAL PHARMACOLOGY AND TOXICOLOGY Studies in rats and monkeys have shown a substantial difference between doses producing tranquilizing, sedative and toxic effects. In rats, conditioned avoidance response was inhibited at an oral dose of 10 mg/kg; sedation was induced at 32 mg/kg; the LD50 was 1320 mg/kg. In monkeys aggressive behavior was reduced at an oral dose of 0.25 mg/kg; sedation (ataxia) was induced at 7.5 mg/kg; the LD50 could not be determined because of the emetic effect of large doses, but the LD50 exceeds 1600 mg/kg. Twenty-four dogs were given clorazepate dipotassium orally in a 22-month toxicity study; doses up to 75 mg/kg were given. Drug-related changes occurred in the liver; weight was increased and cholestasis with minimal hepatocellular damage was found, but lobular architecture remained well preserved. Eighteen rhesus monkeys were given oral doses of clorazepate dipotassium from 3 to 36 mg/kg daily for 52 weeks. All treated animals remained similar to control animals. Although total leucocyte count remained within normal limits it tended to fall in the female animals on the highest doses. Examination of all organs revealed no alterations attributable to clorazepate dipotassium. There was no damage to liver function or structure. Reproduction Studies: Standard fertility, reproduction, and teratology studies were conducted in rats and rabbits. Oral doses in rats up to 150 mg/kg and in rabbits up to 15 mg/kg produced no abnormalities in the fetuses. TRANXENE did not alter the fertility indices or reproductive capacity of adult animals. As expected, the sedative effect of high doses interfered with care of the young by their mothers (see Usage in Pregnancy). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED TRANXENE 3.75 mg scored T-TAB tablets are supplied as blue-colored tablets bearing the letters OV, the distinctive T shape and a two-digit designation, 31: (NDC 67386-301-01). Usage Illustration 7.5 mg scored T-TAB tablets are supplied as peach-colored tablets bearing the letters OV, the distinctive T shape and a two-digit designation, 32: Bottles of 100 (NDC 67386-302-01). Bottles of 500 (NDC 67386-302-05). Usage Illustration 15 mg scored T-TAB tablets are supplied as lavender-colored tablets bearing the letters OV, the distinctive T shape and a two-digit designation, 33: Usage Illustrati on Recommended storage: Protect from moisture. Keep bottle tightly closed. Store at 20-25ºC (68-77ºF). See USP controlled room temperature. Dispense in a USP tight, light-resistant container. T-TAB tablet appearance and shape are registered trademarks of Lundbeck Inc. U.S. Design Pat. No. D-300,879 Manufactured by Abbott Pharmaceuticals PR Ltd. Barceloneta, PR 00617 for: Company logo *Trademark of Sanofi-Aventis ®Trademark of Lundbeck Inc., Deerfield, IL 60015, U.S.A. Revised: April 2009 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:08.885460	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017105s075lbl.pdf', 'application_number': 17105, 'submission_type': 'SUPPL ', 'submission_number': 75}
10,970	company logo ® MOBAN (Molindone Hydrochloride Tablets, USP) Rx only WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug- treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. MOBAN is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION MOBAN (molindone hydrochloride) is a dihydroindolone compound which is not structurally related to the phenothiazines, the butyrophenones or the thioxanthenes. MOBAN is 3-ethyl-6, 7-dihydro-2-methyl-5-(morpholinomethyl) indol-4 (5H)-one hydrochloride. It is a white to off-white crystalline powder, freely soluble in water and alcohol. MOBAN Tablets contain the following inactive ingredients: Calcium sulfate, lactose, magnesium stearate, microcrystalline cellulose and povidone. The 5 mg strength also contains alginic acid, colloidal silicon dioxide and FD&C Yellow 6. The 10 mg strength also contains alginic acid, colloidal silicon dioxide, FD&C Blue 2 and FD&C Red 40. The 25 mg strength also contains alginic acid, colloidal silicon dioxide, D&C Yellow 10, FD&C Blue 2, and FD&C Yellow 6. The 50 mg strength also contains FD&C Blue 2 and sodium starch glycolate. Molindone Hydrochloride is represented by the following structural formula: 1 Reference ID: 2870799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula The empirical formula is C16H24N2O2 • HCl representing a molecular weight of 312.83. CLINICAL PHARMACOLOGY MOBAN has a pharmacological profile in laboratory animals which predominantly resembles that of other antipsychotic agents causing reduction of spontaneous locomotion and aggressiveness, suppression of a conditioned response and antagonism of the bizarre stereotyped behavior and hyperactivity induced by amphetamines. In addition, MOBAN antagonizes the depression caused by the tranquilizing agent tetrabenazine. In human clinical studies an antipsychotic effect is achieved in the absence of muscle relaxing or incoordinating effects. Based on EEG studies, MOBAN exerts its effect on the ascending reticular activating system. Human metabolic studies show MOBAN to be rapidly absorbed and metabolized when given orally. Unmetabolized drug reached a peak blood level at 1.5 hours. Pharmacological effect from a single oral dose persists for 24-36 hours. There are 36 recognized metabolites with less than 2 3% unmetabolized MOBAN being excreted in urine and feces. INDICATIONS AND USAGE MOBAN is indicated for the management of schizophrenia. The efficacy of MOBAN in schizophrenia was established in clinical studies which enrolled newly hospitalized and chronically hospitalized, acutely ill, schizophrenic patients as subjects. CONTRAINDICATIONS MOBAN is contraindicated in severe central nervous system depression (alcohol, barbiturates, narcotics, etc.) or comatose states, and in patients with known hypersensitivity to the drug. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. MOBAN is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. 2 Reference ID: 2870799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to the section on Adverse Reactions.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include, 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. 3 Reference ID: 2870799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. PRECAUTIONS General Some patients receiving MOBAN (molindone hydrochloride) may note drowsiness initially and they should be advised against activities requiring mental alertness until their response to the drug has been established. Increased activity has been noted in patients receiving MOBAN. Caution should be exercised where increased activity may be harmful. MOBAN does not lower the seizure threshold in experimental animals to the degree noted with more sedating antipsychotic drugs. However, in humans convulsive seizures have been reported in a few instances. The physician should be aware that this tablet preparation contains calcium sulfate as an excipient and that calcium ions may interfere with the absorption of preparations containing phenytoin sodium and tetracyclines. MOBAN has an antiemetic effect in animals. A similar effect may occur in humans and may obscure signs of intestinal obstruction or brain tumor. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. MOBAN has not been shown effective in the management of behavioral complications in patients with mental retardation Leukopenia, Neutropenia and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and 4 Reference ID: 2870799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda discontinuation of MOBAN should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue MOBAN and have their WBC followed until recovery. Drug Interactions Potentiation of drugs administered concurrently with MOBAN has not been reported. Additionally, animal studies have not shown increased toxicity when MOBAN is given concurrently with representative members of three classes of drugs (i.e., barbiturates, chloral hydrate and antiparkinson drugs). Pregnancy Studies in pregnant patients have not been carried out. Reproduction studies have been performed in the following animals: Pregnant Rats oral dose— no adverse effect 20 mg/kg/day - 10 days no adverse effect 40 mg/kg/day - 10 days Pregnant Mice oral dose— slight increase resorptions 20 mg/kg/day - 10 days slight increase resorptions 40 mg/kg/day - 10 days Pregnant Rabbits oral dose— no adverse effect 5 mg/kg/day - 12 days no adverse effect 10 mg/kg/day - 12 days no adverse effect 20 mg/kg/day - 12 days Animal reproductive studies have not demonstrated a teratogenic potential. The anticipated benefits must be weighed against the unknown risks to the fetus if used in pregnant patients. Non-teratogenic Effects Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Moban should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 5 Reference ID: 2870799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers Data are not available on the content of MOBAN (molindone hydrochloride) in the milk of nursing mothers. Pediatric Use Use of MOBAN in pediatric patients below the age of twelve years is not recommended because safe and effective conditions for its usage have not been established. ADVERSE REACTIONS CNS Effects The most frequently occurring effect is initial drowsiness that generally subsides with continued usage of the drug or lowering of the dose. Noted less frequently were depression, hyperactivity and euphoria. Neurological Extrapyramidal Symptoms Extrapyramidal symptoms noted below may occur in susceptible individuals and are usually reversible with appropriate management. Akathisia Motor restlessness may occur early. Parkinson Syndrome Akinesia, characterized by rigidity, immobility and reduction of voluntary movements and tremor, have been observed. Occurrence is less frequent than akathisia. Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Tardive Dyskinesia Antipsychotic drugs are known to cause a syndrome of dyskinetic movements commonly referred to as tardive dyskinesia. The movements may appear during treatment or upon withdrawal of treatment and may be either reversible or irreversible (i.e., persistent) upon cessation of further antipsychotic administration. The syndrome is known to have a variable latency for development and the duration of the latency cannot be determined reliably. It is thus wise to assume that any antipsychotic agent has the capacity to induce the syndrome and act accordingly until sufficient data has been collected 6 Reference ID: 2870799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to settle the issue definitively for a specific drug product. In the case of antipsychotics known to produce the irreversible syndrome, the following has been observed. Tardive dyskinesia has appeared in some patients on long-term therapy and has also appeared after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear to be irreversible. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). There may be involuntary movements of extremities. There is no known effective treatment of tardive dyskinesia; antiparkinsonism agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked. It has been reported that fine vermicular movements of the tongue may be an early sign of the syndrome and if the medication is stopped at that time the syndrome may not develop (See WARNINGS). Autonomic Nervous System Occasionally blurring of vision, tachycardia, nausea, dry mouth and salivation have been reported. Urinary retention and constipation may occur particularly if anticholinergic drugs are used to treat extrapyramidal symptoms. One patient being treated with MOBAN experienced priapism which required surgical intervention, apparently resulting in residual impairment of erectile function. Laboratory Tests There have been rare reports of leucopenia and leucocytosis. If such reactions occur, treatment with MOBAN may continue if clinical symptoms are absent. Alterations of blood glucose, B.U.N., and red blood cells have not been considered clinically significant. Metabolic and Endocrine Effects Alteration of thyroid function has not been significant. Amenorrhea has been reported infrequently. Resumption of menses in previously amenorrheic women has been reported. Initially heavy menses may occur. Galactorrhea and gynecomastia have been reported infrequently. Increase in libido has been noted in some patients. Impotence has not been reported. Although both weight gain and weight loss have been in the direction of normal or ideal weight, excessive weight gain has not occurred with MOBAN. Hepatic Effects There have been rare reports of clinically significant alterations in liver function in association with MOBAN use. Cardiovascular Rare, transient, non-specific T wave changes have been reported on E.K.G. Association with a clinical syndrome has not been established. Rarely has significant hypotension been reported. 7 Reference ID: 2870799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ophthalmological Lens opacities and pigmentary retinopathy have not been reported where patients have received MOBAN. In some patients, phenothiazine induced lenticular opacities have resolved following discontinuation of the phenothiazine while continuing therapy with MOBAN. Skin Early, non-specific skin rash, probably of allergic origin, has occasionally been reported. Skin pigmentation has not been seen with MOBAN usage alone. MOBAN has certain pharmacological similarities to other antipsychotic agents. Because adverse reactions are often extensions of the pharmacological activity of a drug, all of the known pharmacological effects associated with other antipsychotic drugs should be kept in mind when MOBAN is used. Upon abrupt withdrawal after prolonged high dosage an abstinence syndrome has not been noted. OVERDOSAGE Symptomatic, supportive therapy should be the rule. Gastric lavage is indicated for the reduction of absorption of MOBAN which is freely soluble in water. Since the adsorption of MOBAN by activated charcoal has not been determined, the use of this antidote must be considered of theoretical value. Emesis in a comatose patient is contraindicated. Additionally, while the emetic effect of apomorphine is blocked by MOBAN in animals, this blocking effect has not been determined in humans. A significant increase in the rate of removal of unmetabolized MOBAN from the body by forced diuresis, peritoneal or renal dialysis would not be expected. (Only 2% of a single ingested dose of MOBAN is excreted unmetabolized in the urine). However, poor response of the patient may justify use of these procedures. While the use of laxatives or enemas might be based on general principles, the amount of unmetabolized MOBAN in feces is less than 1%. Extrapyramidal symptoms have responded to the use of Diphenhydramine (Benadryl®), Amantadine HCl (Symmetrel ®)† and the synthetic anticholinergic antiparkinson agents, (i.e., Artane®‡, Cogentin®§, Akineton®¶). DOSAGE AND ADMINISTRATION Initial and maintenance doses of MOBAN should be individualized. Initial Dosage Schedule The usual starting dosage is 50-75 mg/day. —Increase to 100 mg/day in 3 or 4 days. —Based on severity of symptomatology, dosage may be titrated up or down depending on individual patient response. —An increase to 225 mg/day may be required in patients with severe symptomatology. 8 Reference ID: 2870799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elderly and debilitated patients should be started on lower dosage. Maintenance Dosage Schedule 1. Mild-5 mg-15 mg three or four times a day. 2. Moderate-10 mg-25 mg three or four times a day. 3. Severe-225 mg/day may be required. HOW SUPPLIED MOBAN (molindone hydrochloride) tablets are supplied in bottles of 100 tablets as follows: 5 mg Orange, round, biconvex tablet, one face debossed with “Moban 5”, and the other face plain. NDC 63481-072-70 10 mg Lavender, round, biconvex tablet, one face debossed with “Moban 10”, and the other face plain. NDC 63481-073-70 25 mg Green, round, biconvex tablet, one face debossed with “Moban 25”, and the other face plain with partial bisect. NDC 63481-074-70 50 mg Blue, round, biconvex tablet, one face with partial bisect and debossed with “Moban 50”, and the other face plain. NDC 63481-076-70 Store at 25°C (77°F); excursions permitted to 15°-30°C (59º-86ºF). Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP TIGHTLY CLOSED Benadryl is a registered trademark of Warner-Lambert. † Symmetrel is a registered trademark of Endo Pharmaceuticals Inc. ‡ Artane is a registered trademark of Lederle Laboratories. § Cogentin is a registered trademark of Merck & Co., Inc. ¶ Akineton is a registered trademark of Knoll Laboratories. MOBAN is a registered trademark of Endo Pharmaceuticals Inc. Manufactured for: Endo Pharmaceuticals Inc. company logo Chadds Ford, Pennsylvania 19317 © 2009 Endo Pharmaceuticals Printed in U.S.A. 2005295/December, 2010 9 Reference ID: 2870799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:08.991893	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017111s067lbl.pdf', 'application_number': 17111, 'submission_type': 'SUPPL ', 'submission_number': 67}
10,971	NDA 17-116/S-015 NDA 17-116/S-016 Page 3 CII Methadose® Oral Concentrate (methadone hydrochloride oral concentrate USP) and Methadose® Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) dye-free, sugar-free, unflavored Rx only FOR ORAL USE ONLY CONDITIONS FOR DISTRIBUTION AND USE CONDITIONS FOR DISTRIBUTION AND USE OF METHADONE PRODUCTS FOR THE TREATMENT OF OPIOID ADDICTION Code of Federal Regulations, Title 42, Sec 8 METHADONE PRODUCTS WHEN USED FOR THE TREATMENT OF OPIOID ADDICTION IN DETOXIFICATION OR MAINTENANCE PROGRAMS, SHALL BE DISPENSED ONLY BY OPIOID TREATMENT PROGRAMS (AND AGENCIES, PRACTITIONERS OR INSTITUTIONS BY FORMAL AGREEMENT WITH THE PROGRAM SPONSOR) CERTIFIED BY THE SUBSTANCE ABUSE AND MENTAL HEALTH SERVICES ADMINISTRATION AND APPROVED BY THE DESIGNATED STATE AUTHORITY. CERTIFIED TREATMENT PROGRAMS SHALL DISPENSE AND USE METHADONE IN ORAL FORM ONLY AND ACCORDING TO THE TREATMENT REQUIREMENTS STIPULATED IN THE FEDERAL OPIOID TREATMENT STANDARDS (42 CFR 8.12). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment. FAILURE TO ABIDE BY THE REQUIREMENTS IN THESE REGULATIONS MAY RESULT IN CRIMINAL PROSECUTION, SEIZURE OF THE DRUG SUPPLY, REVOCATION OF THE PROGRAM APPROVAL, AND INJUNCTION PRECLUDING OPERATION OF THE PROGRAM. Regulatory Exceptions to the General Requirement for Certification to Provide Opioid Agonist Treatment: 1. During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21 CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis. 2. During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21 CFR 1306.07(b)). DESCRIPTION Methadose® Oral Concentrate (methadone hydrochloride USP) is supplied as a cherry flavored liquid concentrate. Methadose® Sugar-Free Oral Concentrate (methadone hydrochloride USP) is a dye-free, sugar-free, unflavored liquid concentrate of methadone hydrochloride. Each liquid concentrate This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 4 contains 10 mg of methadone hydrochloride per mL. Methadone hydrochloride (3-heptanone, 6- (dimethylamino)-4, 4-diphenyl-, hydrochloride) is a white, essentially odorless, bitter-tasting crystalline powder. It is very soluble in water, soluble in isopropranolol and in chloroform, and practically insoluble in ether and in glycerine. It is present in Methadose as the racemic mixture. Methadone hydrochloride has a melting point of 235ºC, a pKa of 8.25 in water at 20°C, a solution (1 in 100) pH between 4.5 and 6.5, a partition coefficient of 117 at pH 7.4 in octanol/water and a molecular weight of 345.91. Its molecular formula is C21H27NO•HCl and its structural formula is: Other ingredients of Methadose Oral Concentrate: Artificial cherry flavor, citric acid anhydrous USP, FD&C Red No 40, D&C Red No 33, methylparaben NF, polaxamer 407 NF, propylene glycol USP, propylparaben NF, purified water USP, sodium citrate dihydrate USP, sucrose NF. Other ingredients of Methadose Sugar-Free Oral Concentrate: Citric acid anhydrous USP, purified water USP, sodium benzoate NF. CLINICAL PHARMACOLOGY Mechanism of Action Methadone hydrochloride is a µ agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and sedation and detoxification or maintenance in opioid addiction. The methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals. Pharmacokinetics Absorption Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 to 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to 225 mg the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 5 Distribution Methadone is a lipophilic drug and the steady state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 90%). Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma. Metabolism Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1, 5- dimethyl-3, 3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in urine. Excretion The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. After multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 to 126 L/h and the terminal half-life (T1/2) ranged between 7 to 59 hours. Since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations. Pharmacokinetics in Special Populations Pregnancy There are no pharmacokinetic studies of parenteral methadone in pregnancy. The disposition of oral methadone has been studied in approximately 30 pregnant patients in 2nd and 3rd trimesters. Elimination of methadone was significantly changed in pregnancy. Total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women. The terminal half-life of methadone is decreased during second and third trimesters. The decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may need to be increased or the dosing interval decreased in pregnant patients receiving methadone. (See PRECAUTIONS: Pregnancy, Labor and Delivery, and DOSAGE AND ADMINISTRATION.) Renal Impairment Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree. Methadone is a basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in plasma. Urine acidification has been shown to increase renal elimination of methadone. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for increasing methadone or metabolite elimination. Hepatic Impairment Methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized by hepatic pathways, therefore patients with liver impairment may be at risk of accumulating methadone after multiple dosing. Gender The pharmacokinetics of methadone have not been evaluated for gender specificity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 6 Race The pharmacokinetics of methadone have not been evaluated for race specificity. Geriatric The pharmacokinetics of methadone have not been evaluated in the geriatric population. Pediatric The pharmacokinetics of methadone have not been evaluated in the pediatric population. Drug Interactions (see PRECAUTIONS, Drug Interactions) Methadone undergoes hepatic N-demethylation by cytochrome P-450 isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with inducers of these enzymes may result in more rapid methadone metabolism, and potentially, decreased effects of methadone. Conversely, administration with inhibitors may reduce metabolism and potentiate methadone’s effects. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential. Clinicians are advised to evaluate individual response to drug therapy. INDICATIONS AND USAGE 1. Detoxification treatment of opioid addiction (heroin or other morphine-like drugs). 2. Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. NOTE Outpatient maintenance and outpatient detoxification treatment may be provided only by Opioid Treatment Programs (OTPs) certified by the Federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA). This does not preclude the maintenance treatment of a patient with concurrent opioid addiction who is hospitalized for conditions other than opioid addiction and who requires temporary maintenance during the critical period of his/her stay, or of a patient whose enrollment has been verified in a program which has been certified for maintenance treatment with methadone. CONTRAINDICATIONS Methadose is contraindicated in patients with a known hypersensitivity to methadone hydrochloride or any other ingredient in Methadose. Methadose is contraindicated in any situation where opioids are contraindicated such as: patients with respiratory depression (in the absence of resuscitative equipment or in unmonitored settings), and in patients with acute bronchial asthma or hypercarbia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 7 WARNINGS Methadose® and Methadose® Sugar-Free are for oral administration only. The preparation must not be injected. Methadose® and Methadose® Sugar-Free, if dispensed, should be packaged in child-resistant containers and kept out of reach of children to prevent accidental ingestion. Cardiac Conduction Effects This information is provided to alert the prescribing physician, and is not intended to deter the appropriate use of methadone in patients with a history of cardiac disease. Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Although most cases involve patients being treated for pain with large, multiple daily doses of methadone, cases have been reported in patients receiving doses commonly used in maintenance treatment of opioid addiction. In most of the cases seen at typical maintenance doses, concomitant medications and/or clinical conditions such as hypokalemia are noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction disease, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. Patients developing QT prolongation while on methadone treatment should be evaluated for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism. The potential risks of methadone, including the risk of life-threatening arrhythmias, should be weighed against the risks of discontinuing methadone treatment. In the patient being treated for opiate dependence with methadone maintenance therapy, these risks include a very high likelihood of relapse to illicit drug use following methadone discontinuation. The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied. The potential risks of methadone should be weighed against the substantial morbidity and mortality associated with untreated opioid addiction. Respiratory Depression Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadose should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 8 depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. Incomplete Cross-tolerance between Methadone and other Opioids Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross- tolerance is of particular concern for patients tolerant to other µ-opioid agonists who are being converted to methadone, thus making determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Misuse, Abuse, and Diversion of Opioids Methadone is a mu-agonist opioid with an abuse liability similar to morphine and is a Schedule II controlled substance. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when dispensing Methadose in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Interactions with other CNS Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with methadone may experience respiratory depression, hypotension, profound sedation, or coma (see PRECAUTIONS). Interactions with Alcohol and Drugs of Abuse Methadone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Deaths associated with illicit use of methadone frequently have involved concomitant benzodiazepine abuse. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal-fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential. Acute Abdominal Conditions This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 9 The administration of opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Hypotensive Effect The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion). PRECAUTIONS Methadose should be used with caution in elderly and debilitated patients; patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease; and in patients with comorbid conditions or concomitant medications which may predispose to dysrhythmia or reduced ventilatory drive. Drug Interactions In vitro results suggest that methadone undergoes hepatic N-demethylation by cytochrome P450 enzymes, principally CYP3A4, CYP2B6, CYP2C19 and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with inducers of these enzymes may result in a more rapid metabolism and potential for decreased effects of methadone, whereas administration with inhibitors may reduce metabolism and potentiate methadone’s effects. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy. Opioid Antagonists, Mixed Agonist/Antagonists, and Partial Agonists As with other µ-agonists, patients maintained on methadone may experience withdrawal symptoms when given these agents. Examples of such agents are naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine. Anti-retroviral Agents Abacavir, amprenavir, efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination – Coadministration of these anti-retroviral agents resulted in increased clearance or decrease plasma levels of methadone. Methadone-maintained patients beginning treatment with above antiretroviral drugs should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly. Didanosine and Stavudine – Experimental evidence demonstrated that methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered. Zidovudine – Experimental evidence demonstrated that methadone increased the area under the concentration-time curve (AUC) of zidovudine which could result in toxic effects. Cytochrome P450 Inducers Methadone-maintained patients beginning treatment with CYP3A4 inducers should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly. The following This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 10 drug interactions were reported following coadministration of methadone with inducers of cytochrome P450 enzymes: Rifampin – In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms. Phenytoin – In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i.d. initially for 1 day followed by 300 mg QD for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin administration. St. John’s Wort, Phenobarbital, Carbamazepine Administration of methadone along with other CYP3A4 inducers may result in withdrawal symptoms. Cytochrome P450 Inhibitors Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. The expected clinical results would be increased or prolonged opioid effects. Thus, methadone-treated patients coadministered strong inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole) with methadone should be carefully monitored and dosage adjustment should be undertaken if warranted. Some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine) may increase methadone plasma levels upon coadministration with methadone and result in increased opiate effects and/or toxicity. Voriconazole – Repeat dose administration of oral voriconazole (400mg Q12h for 1 day, then 200mg Q12h for 4 days) increased the Cmax and AUC of R-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg QD). The Cmax and AUC of (S)- methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed. Others Monoamine Oxidase (MAO) Inhibitors – Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone. However, if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small, incremental doses of methadone are administered over the course of several hours while the patient's condition and vital signs are under careful observation. Desipramine – Blood levels of desipramine have increased with concurrent methadone administration. Potentially Arrhythmogenic Agents Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 11 use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Caution should also be exercised when prescribing Methadose concomitantly with drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval. These drugs include diuretics, laxatives, and, in rare cases, mineralocorticoid hormones. Interactions with Alcohol and Drugs of Abuse Methadone may be expected to have additive effects when used in conjunction with alcohol, other opioids or CNS depressants, or with illicit drugs that cause central nervous system depression. Deaths have been reported when methadone has been abused in conjunction with benzodiazepines. Anxiety – Since methadone as used by tolerant subjects at a constant maintenance dosage does not act as a tranquilizer, patients who are maintained on this drug will react to life problems and stresses with the same symptoms of anxiety as do other individuals. The physician should not confuse such symptoms with those of narcotic abstinence and should not attempt to treat anxiety by increasing the dose of methadone. The action of methadone in maintenance treatment is limited to the control of narcotic withdrawal symptoms and is ineffective for relief of general anxiety. Acute Pain – Maintenance patients on a stable dose of methadone who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their ongoing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. Due to the opioid tolerance induced by methadone, when opioids are required for management of acute pain in methadone patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients. Physical Dependence Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence is expected during opioid agonist therapy of opioid addiction. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Medically Supervised Withdrawal). Special-Risk Patients – Methadone should be given with caution, and the initial dose reduced, in certain patients such as the elderly and debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy, or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression requires added vigilance. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 12 Information for Patients • Patients should be cautioned that methadone, like all opioids, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving or operating machinery. • Patients should be cautioned that methadone, like other opioids, may produce orthostatic hypotension in ambulatory patients. • Patients should be cautioned that alcohol and other CNS depressants may produce an additive CNS depression when taken with this product and should be avoided. • Patients should be instructed to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, or syncope) when taking Methadose. • Patients initiating treatment with methadone should be reassured that the dose of methadone will “hold” for longer periods of time as treatment progresses. • Patients seeking to discontinue treatment should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis – The results of carcinogenicity assessment in B6C2F1 mice and Fischer 344 rats following dietary administration of two doses of methadone HCl have been published. Mice consumed 15 mg/kg/day or 60 mg/kg/day methadone for two years. These doses were approximately 0.6 and 2.5 times a human daily oral dose of 120 mg/day on a body surface area basis (mg/m2). There was a significant increase in pituitary adenomas in female mice treated with 15 mg/kg/day but not with 60 mg/kg/day. Under the conditions of the assay, there was no clear evidence for a treatment-related increase in the incidence of neoplasms in male rats. Due to decreased food consumption in males at the high dose, male rats consumed 16 mg/kg/day and 28 mg/kg/day of methadone for two years. These doses were approximately 1.3 and 2.3 times a human daily oral dose of 120 mg/day, based on body surface area comparison. In contrast, female rats consumed 46 mg/kg/day or 88 mg/kg/day for two years. These doses were approximately 3.7 and 7.1 times a human daily oral dose of 120 mg/day, based on body surface area comparison. Under the conditions of the assay, there was no clear evidence for a treatment-related increase in the incidence of neoplasms in either male or female rats. Mutagenesis – There are several published reports on the potential genetic toxicity of methadone. Methadone tested negative in tests for chromosome breakage and disjunction and sex-linked recessive lethal gene mutations in germ cells of Drosophila using feeding and injection procedures. In contrast, methadone tested positive in the in vivo mouse dominant lethal assay and the in vivo mammalian spermatogonial chromosome aberration test. Additionally, methadone tested positive in the E.coli DNA repair system and Neurospora crassa and mouse lymphoma forward mutation assays. Fertility – Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 13 and abnormalities in sperm morphology have been reported. Published animal studies provide additional data indicating that methadone treatment of males can alter reproductive function. Methadone produces a significant regression of sex accessory organs and testes of male mice and rats. Additional data have been published indicating that methadone treatment of male rats (once a day for three consecutive days) increased embryolethality and neonatal mortality. Examination of uterine contents of methadone-naive female mice bred to methadone-treated mice indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states. Pregnancy Teratogenic Effects – Pregnancy Category C. There are no controlled studies of methadone use in pregnant women. However, an expert review of published data on experiences with methadone use during pregnancy by the Teratogen Information System (TERIS) concluded that maternal use of methadone during pregnancy as part of a supervised, therapeutic regimen is unlikely to pose a substantial teratogenic risk (quantity and quality of data assessed as “limited to fair”). However, the data are insufficient to state that there is no risk (TERIS, last reviewed October, 2002). Pregnant women involved in methadone maintenance programs have been reported to have significantly improved prenatal care leading to significantly reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality. Several factors complicate the interpretation of investigations of the children of women who take methadone during pregnancy. These include the maternal use of illicit drugs, other maternal factors such as nutrition, infection, and psychosocial circumstances, limited information regarding dose and duration of methadone use during pregnancy, and the fact that most maternal exposure appears to occur after the first trimester of pregnancy. Reported studies have generally compared the benefit of methadone to the risk of untreated addiction to illicit drugs. Methadone has been detected in amniotic fluid and cord plasma at concentrations proportional to maternal plasma and in newborn urine at lower concentrations than corresponding maternal urine. A retrospective series of 101 pregnant, opiate-dependent women who underwent inpatient opiate detoxification with methadone did not demonstrate any increased risk of miscarriage in the 2nd trimester or premature delivery in the 3rd trimester. Several studies have suggested that infants born to narcotic-addicted women treated with methadone during all or part of pregnancy have been found to have decreased fetal growth with reduced birth weight, length, and/or head circumference compared to controls. This growth deficit does not appear to persist into later childhood. However, children born to women treated with methadone during pregnancy have been shown to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests. Methadone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Additional information on the potential risks of methadone may be derived from animal data. Methadone does not appear to be teratogenic in the rat or rabbit models. However, following large doses, methadone produced teratogenic effects in the guinea pig, hamster and mouse. One published study in pregnant hamsters indicated that a single subcutaneous dose of methadone ranging from 31 to 185 mg/kg (the 31 mg/kg dose is approximately 2 times a human daily oral dose of 120 mg/day on a mg/m2 basis) on day 8 of gestation resulted in a decrease in the number of fetuses per litter and an increase in the percentage of fetuses exhibiting congenital malformations described as exencephaly, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 14 cranioschisis, and “various other lesions.” The majority of the doses tested also resulted in maternal death. In another study, a single subcutaneous dose of 22 to 24 mg/kg methadone (estimated exposure was approximately equivalent to a human daily oral dose of 120 mg/day on a mg/m2 basis) administered on day 9 of gestation in mice also produced exencephaly in 11% of the embryos. However, no effects were reported in rats and rabbits at oral doses up to 40 mg/kg (estimated exposure was approximately 3 and 6 times, respectively, a human daily oral dose of 120 mg/day on a mg/m2 basis) administered during days 6 to 15 and 6 to 18, respectively. Nonteratogenetic Effects – Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. Onset of withdrawal symptoms in infants is usually in the first days after birth. Withdrawal signs in the newborn include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the maternal dose or the duration of maternal exposure. The duration of the withdrawal signs may vary from a few days to weeks or even months. There is no consensus on the appropriate management of infant withdrawal. There are conflicting reports on whether SIDS occurs with an increased incidence in infants born to women treated with methadone during pregnancy. Abnormal fetal nonstress tests (NSTs) have been reported to occur more frequently when the test is performed 1 to 2 hours after a maintenance dose of methadone in late pregnancy compared to controls. Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone prior to mating. In these studies, the female rodents were not treated with methadone, indicating paternally-mediated developmental toxicity. Specifically, methadone administered to the male rat prior to mating with methadone-naïve females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. Further, behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals, suggesting that paternal methadone exposure can produce physiological and behavioral changes in progeny in this model. Other animal studies have reported that perinatal exposure to opioids including methadone alters neuronal development and behavior in the offspring. Perinatal methadone exposure in rats has been linked to alterations in learning ability, motor activity, thermal regulation, nociceptive responses and sensitivity to drugs. Additional animal data demonstrates evidence for neurochemical changes in the brains of methadone-treated offspring, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems. Additional studies demonstrated that methadone treatment of male rats for 21 to 32 days prior to mating with methadone-naïve females did not produce any adverse effects, suggesting that prolonged methadone treatment of the male rat resulted in tolerance to the developmental toxicities noted in the progeny. Mechanistic studies in this rat model suggest that the developmental effects of “paternal” methadone on the progeny appear to be due to decreased testosterone production. These animal data mirror the reported clinical findings of decreased testosterone levels in human males on methadone maintenance therapy for opioid addiction and in males receiving chronic intraspinal opioids. Clinical Pharmacology – Pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery. Dosage adjustment using higher doses or administering the daily dose in divided This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 15 doses may be necessary in pregnant women treated with Methadose. [See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION]. Labor and Delivery As with all opioids, administration of this product to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. Methadone is not recommended for obstetric analgesia because its long duration of action increases the probability of respiratory depression in the newborn. Narcotics with mixed agonist-antagonist properties should not be used for pain control during labor in patients chronically treated with methadone as they may precipitate acute withdrawal. Methadone is secreted into human milk. The safety of breastfeeding while taking oral methadone is controversial. At maternal oral doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 µg/L in milk have been reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 µg/kg/day which is approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone. Women on high dose methadone maintenance, who are already breast feeding, should be counseled to wean breast-feeding gradually in order to prevent neonatal abstinence syndrome. Methadone-treated mothers considering nursing an opioid-naïve infant should be counseled regarding the presence of methadone in breast milk. Because of the potential for serious adverse reactions in nursing infants from methadone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother, and weighing the risk of methadone against the risk of maternal illicit drug use. Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Geriatric Use Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Renal Impairment The use of methadone has not been extensively evaluated in patients with renal insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 16 Hepatic Impairment The use of methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized in the liver and patients with liver impairment may be at risk of accumulating methadone after multiple dosing. Gender The use of methadone has not been evaluated for gender specificity. ADVERSE REACTIONS Heroin Withdrawal During the induction phase of methadone maintenance treatment, patients are being withdrawn from heroin and may therefore show typical withdrawal symptoms, which should be differentiated from methadone-induced side effects. They may exhibit some or all of the following symptoms associated with acute withdrawal from heroin or other opiates: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilliness alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss. Initial Administration The initial methadone dose should be carefully titrated to the individual. Too rapid titration for the patient’s sensitivity is more likely to produce adverse effects. The major hazards of methadone, are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, and death have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable. Other adverse reactions include the following: Body as a Whole – asthenia (weakness), edema, headache Cardiovascular – arrhythmias, bigeminal rhythms, bradycardia, extrasystoles, tachycardia, torsade de pointes, ventricular fibrillation, ventricular tachycardia, ECG abnormalities, prolonged QT interval, T- wave inversion, cardiomyopathy, flushing, heart failure, hypotension, palpitations, phlebitis, syncope Digestive – abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis Hematologic and Lymphatic – reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis Metabolic and Nutritional – hypokalemia, hypomagnesemia, weight gain Nervous – agitation, confusion, seizures, disorientation, dysphoria, euphoria, insomnia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 17 Respiratory – pulmonary edema Skin and Appendages – pruritis, urticaria, other skin rashes, and rarely, hemorrhagic urticaria Special Senses – visual disturbances Urogenital – antidiuretic effect, amenorrhea, urinary retention or hesitancy, reduced libido and/or potency Maintenance on a Stabilized Dose – During prolonged administration of methadone, as in a methadone maintenance treatment program, there is usually a gradual, yet progressive, disappearance of side effects over a period of several weeks. However, constipation and sweating often persist. DRUG ABUSE AND DEPENDENCE Methadose® contains methadone, a potent Schedule II opioid agonist. Schedule II opioid substances, which also include hydromorphone, morphine, oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. Abuse of Methadose poses a risk of overdose and death. This risk is increased with concurrent abuse of Methadose with alcohol and other substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Since Methadose® may be diverted for non-medical use, careful record keeping of ordering and dispensing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Methadose®, when used for the treatment of opioid addiction in detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration (and agencies, practitioners or institutions by formal agreement with the program sponsor). OVERDOSAGE Signs and Symptoms Serious overdosage of methadone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, maximally constricted pupils, skeletal-muscle flaccidity, cold and clammy skin, and sometimes, bradycardia and hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. If a non-tolerant This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 18 person, takes a large dose of methadone, effective opioid antagonists are available to counteract the potentially lethal respiratory depression. The physician must remember, however, that methadone is a long-acting depressant (36 to 48 hours), whereas opioid antagonists act for much shorter periods (one to three hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and may need to be treated repeatedly with the narcotic antagonist. If the diagnosis is correct and respiratory depression is due only to overdosage of methadone, the use of other respiratory stimulants is not indicated. Opioid antagonists should not be administered in the absence of clinically significant respiratory or cardiovascular depression. In an individual physically dependent on opioids, the administration of the usual dose of an opioid antagonist may precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. If antagonists must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist. Intravenously administered naloxone or nalmefene may be used to reverse signs of intoxication. Because of the relatively short half-life of naloxone as compared with methadone, repeated injections may be required until the status of the patient remains satisfactory. Naloxone may also be administered by continuous intravenous infusion. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. DOSAGE AND ADMINISTRATION Methadone differs from many other opioid agonists in several important ways. Methadone's pharmacokinetic properties, coupled with high interpatient variability in its absorption, metabolism, and relative analgesic potency, necessitate a cautious and highly individualized approach to prescribing. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration. While methadone’s duration of analgesic action (typically 4 to 8 hours) in the setting of single-dose studies approximates that of morphine, methadone’s plasma elimination half-life is substantially longer than that of morphine (typically 8 to 59 hours vs. 1 to 5 hours). Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. Also, with repeated dosing, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations. For these reasons, steady-state plasma concentrations, and full analgesic effects, are usually not attained until 3 to 5 days of dosing. Additionally, incomplete cross-tolerance between µ-opioid agonists makes determination of dosing during opioid conversion complex. The complexities associated with methadone dosing can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 19 Detoxification and Maintenance Treatment of Opiate Dependence For detoxification and maintenance of opiate dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration. Induction/Initial Dosing The initial methadone dose should be administered, under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. Initially, a single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg. If same-day dosing adjustments are to be made, the patient should be asked to wait 2 to 4 hours for further evaluation, when peak levels have been reached. An additional 5 to 10 mg of methadone may be provided if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Dose adjustments should be made over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). Dose adjustment should be cautious; deaths have occurred in early treatment due to the cumulative effects of the first several days’ dosing. Patients should be reminded that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate. Initial doses should be lower for patients whose tolerance is expected to be low at treatment entry. Loss of tolerance should be considered in any patient who has not taken opioids for more than 5 days. Initial doses should not be determined by previous treatment episodes or dollars spent per day on illicit drug use. For Short-term Detoxification For patients preferring a brief course of stabilization followed by a period of medically supervised withdrawal, it is generally recommended that the patient be titrated to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. Stabilization can be continued for 2 to 3 days, after which the dose of methadone should be gradually decreased. The rate at which methadone is decreased should be determined separately for each patient. The dose of methadone can be decreased on a daily basis or at 2-day intervals, but the amount of intake should remain sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20% of the total daily dose may be tolerated. In ambulatory patients, a somewhat slower schedule may be needed. For Maintenance Treatment Patients in maintenance treatment should be titrated to a dose at which opioid symptoms are prevented for 24 hours, drug hunger or craving is reduced, the euphoric effects of self-administered opioids are blocked or attenuated, and the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day. For Medically Supervised Withdrawal After a Period of Maintenance Treatment There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14- day intervals should elapse between dose reductions. Patients should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-116/S-015 NDA 17-116/S-016 Page 20 HOW SUPPLIED Methadose® Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry-flavored liquid concentrate in one-liter bottles (NDC 0406-0527-10). Methadose® Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate in one-liter bottles (NDC 0406- 8725-10). Dispense in tight containers, protected from light. Store at 20° to 25° C (68° to 77° F) [see USP Controlled Room Temperature]. Methadose® is a registered trademark of Mallinckrodt Inc. Mallinckrodt Inc. St. Louis, MO 63134, U.S.A. Rev 031805 W This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:09.260503	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017116s015,016lbl.pdf', 'application_number': 17116, 'submission_type': 'SUPPL ', 'submission_number': 15}
10,969	Tranxene* T-TAB® Tablets (clorazepate dipotassium tablets, USP) Rx only DESCRIPTION Chemically, TRANXENE is a benzodiazepine. The empirical formula is C16H11ClK2N2O4; the molecular weight is 408.92; 1H-1, 4-Benzodiazepine-3-carboxylic acid, 7-chloro-2,3 dihydro-2-oxo-5-phenyl-, potassium salt compound with potassium hydroxide (1:1) and the Chemical structure of Tranxene The compound occurs as a fine, light yellow, practically odorless powder. It is insoluble in the common organic solvents, but very soluble in water. Aqueous solutions are unstable, clear, light yellow, and alkaline. TRANXENE T-TAB tablets contain either 3.75 mg, 7.5 mg or 15 mg of clorazepate dipotassium for oral administration. Inactive ingredients for TRANXENE T-TAB Tablets: Colloidal silicon dioxide, FD&C Blue No. 2 (3.75 mg only), FD&C Yellow No. 6 (7.5 mg only), FD&C Red No. 3 (15 mg only), magnesium oxide, magnesium stearate, microcrystalline cellulose, potassium carbonate, potassium chloride, and talc. CLINICAL PHARMACOLOGY Pharmacologically, clorazepate dipotassium has the characteristics of the benzodiazepines. It has depressant effects on the central nervous system. The primary metabolite, nordiazepam, quickly appears in the blood stream. The serum half-life is about 2 days. The drug is metabolized in the liver and excreted primarily in the urine. Studies in healthy men have shown that clorazepate dipotassium has depressant effects on the central nervous system. Prolonged administration of single daily doses as high as 120 mg was without toxic effects. Abrupt cessation of high doses was followed in some patients by nervousness, insomnia, irritability, diarrhea, muscle aches, or memory impairment. Since orally administered clorazepate dipotassium is rapidly decarboxylated to form nordiazepam, there is essentially no circulating parent drug. Nordiazepam, the primary metabolite, quickly appears in the blood and is eliminated from the plasma with an apparent half-life of about 40 to 50 hours. Plasma levels of nordiazepam increase proportionally with TRANXENE dose and show moderate accumulation with repeated administration. The protein binding of nordiazepam in plasma is high (97-98%). Within 10 days after oral administration of a 15 mg (50µCi) dose of 14C-TRANXENE to two This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda volunteers, 62-67% of the radioactivity was excreted in the urine and 15-19% was eliminated in the feces. Both subjects were still excreting measurable amounts of radioactivity in the urine (about l% of the 14C-dose) on day ten. Nordiazepam is further metabolized by hydroxylation. The major urinary metabolite is conjugated oxazepam (3-hydroxynordiazepam), and smaller amounts of conjugated p hydroxynordiazepam and nordiazepam are also found in the urine. INDICATIONS AND USAGE TRANXENE is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. TRANXENE tablets are indicated as adjunctive therapy in the management of partial seizures. The effectiveness of TRANXENE tablets in long-term management of anxiety, that is, more than 4 months, has not been assessed by systematic clinical studies. Long-term studies in epileptic patients, however, have shown continued therapeutic activity. The physician should reassess periodically the usefulness of the drug for the individual patient. TRANXENE tablets are indicated for the symptomatic relief of acute alcohol withdrawal. CONTRAINDICATIONS TRANXENE tablets are contraindicated in patients with a known hypersensitivity to the drug and in those with acute narrow angle glaucoma. WARNINGS Use in Depressive Neuroses or Psychotic Reactions: TRANXENE tablets are not recommended for use in depressive neuroses or in psychotic reactions. Use in Children: Because of the lack of sufficient clinical experience, TRANXENE tablets are not recommended for use in patients less than 9 years of age. Interference with Psychomotor Performance: Patients taking TRANXENE tablets should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating dangerous machinery including motor vehicles. Concomitant Use with CNS Depressants: Since TRANXENE has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS depressant drugs, and cautioned that the effects of alcohol may be increased. Physical and Psychological Dependence: Withdrawal symptoms (similar in character to those noted with barbiturates and alcohol) have occurred following abrupt discontinuance of clorazepate. Withdrawal symptoms associated with the abrupt discontinuation of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda benzodiazepines have included convulsions, delirium, tremor, abdominal and muscle cramps, vomiting, sweating, nervousness, insomnia, irritability, diarrhea, and memory impairment. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation of clorazepate should generally be avoided and a gradual dosage tapering schedule followed. Caution should be observed in patients who are considered to have a psychological potential for drug dependence. Evidence of drug dependence has been observed in dogs and rabbits which was characterized by convulsive seizures when the drug was abruptly withdrawn or the dose was reduced; the syndrome in dogs could be abolished by administration of clorazepate. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including TRANXENE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table1: Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Relative Risk: Risk Difference: with Events Per Patients with Incidence of Additional Drug 1000 Patients Events Per Events in Drug Patients with 1000 Patients/Incidence Events Per 1000 Patients in Placebo Patients Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing TRANXENE or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self- harm. Behaviors of concern should be reported immediately to healthcare providers. Usage in Pregnancy: An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Clorazepate dipotassium, a benzodiazepine derivative, has not been studied adequately to determine whether it, too, may be associated with an increased risk of fetal abnormality. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug. To provide information regarding the effects of in utero exposure to TRANXENE, physicians are advised to recommend that pregnant patients taking TRANXENE enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usage during Lactation: TRANXENE tablets should not be given to nursing mothers since it has been reported that nordiazepam is excreted in human breast milk. PRECAUTIONS In those patients in which a degree of depression accompanies the anxiety, suicidal tendencies may be present and protective measures may be required. The least amount of drug that is feasible should be available to the patient. Patients taking TRANXENE tablets for prolonged periods should have blood counts and liver function tests periodically. The usual precautions in treating patients with impaired renal or hepatic function should also be observed. In elderly or debilitated patients, the initial dose should be small, and increments should be made gradually, in accordance with the response of the patient, to preclude ataxia or excessive sedation. Information for Patients: To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is essential that they consult with their physician before either increasing the dose or abruptly discontinuing this drug. Patients, their caregivers, and families should be counseled that AEDs, including TRANXENE, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 (see Usage in Pregnancy). Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with clorazepate dipotassium and should counsel them in its appropriate use. A patient Medication Guide is available for TRANXENE. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is available at www.lundbeckinc.com. Pediatric Use: See WARNINGS. Geriatric Use: Clinical studies of TRANXENE were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects. Elderly or debilitated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients may be especially sensitive to the effects of all benzodiazepines, including TRANXENE. In general, elderly or debilitated patients should be started on lower doses of TRANXENE and observed closely, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy. Dose adjustments should also be made slowly, and with more caution in this patient population (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS The side effect most frequently reported was drowsiness. Less commonly reported (in descending order of occurrence) were: dizziness, various gastrointestinal complaints, nervousness, blurred vision, dry mouth, headache, and mental confusion. Other side effects included insomnia, transient skin rashes, fatigue, ataxia, genitourinary complaints, irritability, diplopia, depression, tremor, and slurred speech. There have been reports of abnormal liver and kidney function tests and of decrease in hematocrit. Decrease in systolic blood pressure has been observed. To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck Inc. at 1-800-455 1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DOSAGE AND ADMINISTRATION For the symptomatic relief of anxiety: TRANXENE T-TAB tablets are administered orally in divided doses. The usual daily dose is 30 mg. The dose should be adjusted gradually within the range of 15 to 60 mg daily in accordance with the response of the patient. In elderly or debilitated patients it is advisable to initiate treatment at a daily dose of 7.5 to 15 mg. TRANXENE tablets may also be administered in a single dose daily at bedtime; the recommended initial dose is 15 mg. After the initial dose, the response of the patient may require adjustment of subsequent dosage. Lower doses may be indicated in the elderly patient. Drowsiness may occur at the initiation of treatment and with dosage increment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For the symptomatic relief of acute alcohol withdrawal: The following dosage schedule is recommended: 1st 24 hours followed by (Day 1) doses 30 mg initially; 30 to 60 mg in divided 2nd 24 hours doses (Day 2) 45 to 90 mg in divided 3rd 24 hours divided doses (Day 3) 22.5 to 45 mg in Day 4 doses 15 to 30 mg in divided Thereafter, gradually reduce the daily dose to 7.5 to 15 mg. Discontinue drug therapy as soon as patient’s condition is stable. The maximum recommended total daily dose is 90 mg. Avoid excessive reductions in the total amount of drug administered on successive days. As an Adjunct to Antiepileptic Drugs: In order to minimize drowsiness, the recommended initial dosages and dosage increments should not be exceeded. Adults: The maximum recommended initial dose in patients over 12 years old is 7.5 mg three times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 90 mg/day. Children (9-12 years): The maximum recommended initial dose is 7.5 mg two times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 60 mg/day. DRUG INTERACTIONS If TRANXENE is to be combined with other drugs acting on the central nervous system, careful consideration should be given to the pharmacology of the agents to be employed. Animal experience indicates that clorazepate dipotassium prolongs the sleeping time after hexobarbital or after ethyl alcohol, increases the inhibitory effects of chlorpromazine, but does not exhibit monoamine oxidase inhibition. Clinical studies have shown increased sedation with concurrent hypnotic medications. The actions of the benzodiazepines may be potentiated by barbiturates, narcotics, phenothiazines, monoamine oxidase inhibitors or other antidepressants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If TRANXENE tablets are used to treat anxiety associated with somatic disease states, careful attention must be paid to possible drug interaction with concomitant medication. In bioavailability studies with normal subjects, the concurrent administration of antacids at therapeutic levels did not significantly influence the bioavailability of TRANXENE tablets. OVERDOSAGE Overdosage is usually manifested by varying degrees of CNS depression ranging from slight sedation to coma. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. The treatment of overdosage should consist of the general measures employed in the management of overdosage of any CNS depressant. Gastric evacuation either by the induction of emesis, lavage, or both, should be performed immediately. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. Hypotension, though rarely reported, may occur with large overdoses. In such cases the use of agents such as norepinephrine bitartrate injection, USP or metaraminol bitartrate injection, USP should be considered. While reports indicate that individuals have survived overdoses of clorazepate dipotassium as high as 450 to 675 mg, these doses are not necessarily an accurate indication of the amount of drug absorbed since the time interval between ingestion and the institution of treatment was not always known. Sedation in varying degrees was the most common physiological manifestation of clorazepate dipotassium overdosage. Deep coma when it occurred was usually associated with the ingestion of other drugs in addition to clorazepate dipotassium. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use. ANIMAL PHARMACOLOGY AND TOXICOLOGY Studies in rats and monkeys have shown a substantial difference between doses producing tranquilizing, sedative and toxic effects. In rats, conditioned avoidance response was inhibited at an oral dose of 10 mg/kg; sedation was induced at 32 mg/kg; the LD50 was 1320 mg/kg. In monkeys aggressive behavior was reduced at an oral dose of 0.25 mg/kg; sedation (ataxia) was induced at 7.5 mg/kg; the LD50 could not be determined because of the emetic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda effect of large doses, but the LD50 exceeds 1600 mg/kg. Twenty-four dogs were given clorazepate dipotassium orally in a 22-month toxicity study; doses up to 75 mg/kg were given. Drug-related changes occurred in the liver; weight was increased and cholestasis with minimal hepatocellular damage was found, but lobular architecture remained well preserved. Eighteen rhesus monkeys were given oral doses of clorazepate dipotassium from 3 to 36 mg/kg daily for 52 weeks. All treated animals remained similar to control animals. Although total leucocyte count remained within normal limits it tended to fall in the female animals on the highest doses. Examination of all organs revealed no alterations attributable to clorazepate dipotassium. There was no damage to liver function or structure. Reproduction Studies: Standard fertility, reproduction, and teratology studies were conducted in rats and rabbits. Oral doses in rats up to 150 mg/kg and in rabbits up to 15 mg/kg produced no abnormalities in the fetuses. TRANXENE did not alter the fertility indices or reproductive capacity of adult animals. As expected, the sedative effect of high doses interfered with care of the young by their mothers (see Usage in Pregnancy). HOW SUPPLIED TRANXENE 3.75 mg scored T-TAB tablets are supplied as blue-colored tablets bearing the letters OV, the distinctive T shape and a two-digit designation, 31: (NDC 67386-301-01). Tranxene T-TAB tablets 7.5 mg scored T-TAB tablets are supplied as peach-colored tablets bearing the letters OV, the distinctive T shape and a two-digit designation, 32: Bottles of 100 (NDC 67386-302-01). Tranxene T-TAB tablets 15 mg scored T-TAB tablets are supplied as lavender-colored tablets bearing the letters OV, the distinctive T shape and a two-digit designation, 33: Bottles of 100 (NDC 67386-303-01). Tranxene T-TAB tablets This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Recommended storage: Protect from moisture. Keep bottle tightly closed. Store at 20-25ºC (68-77ºF). See USP controlled room temperature. Dispense in a USP tight, light-resistant container. T-TAB tablet appearance and shape are registered trademarks of Lundbeck Inc. U.S. Design Pat. No. D-300,879 Manufactured by: Abbott Pharmaceuticals PR Ltd. Barceloneta, PR 00617 Lundbeck Trademark of Sanofi-Aventis ®Trademark of Lundbeck Inc. Revised: May 2010 component number This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE Tranxene (TRAN-zeen) T-TAB® (clorazepate dipotassium) tablets Read this Medication Guide before you start taking TRANXENE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about TRANXENE? Do not stop taking TRANXENE without first talking to your healthcare provider. Stopping TRANXENE suddenly can cause serious problems. TRANXENE can cause serious side effects, including: 1. TRANXENE can make you sleepy or dizzy and can slow your thinking and motor skills • Do not drive, operate heavy machinery, or do other dangerous activities until you know how TRANXENE affects you. • Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking TRANXENE without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, TRANXENE may make your sleepiness or dizziness much worse. 2. TRANXENE can cause abuse and dependence. • Do not stop taking TRANXENE all of a sudden. Stopping TRANXENE suddenly can cause seizures that do not stop, hearing or seeing things that are not there (hallucinations), shaking, and stomach and muscle cramps. o Talk to your doctor about slowly stopping TRANXENE to avoid getting sick with withdrawal symptoms. o Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. TRANXENE is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep TRANXENE in a safe place to prevent misuse and abuse. Selling or giving away TRANXENE may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs. 3. TRANXENE may harm your unborn or developing baby. Medicines like TRANXENE can cause birth defects. Talk with your healthcare provider if you are pregnant or plan to become pregnant. Tell your healthcare provider right away if you become This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pregnant while taking TRANXENE. You and your healthcare provider should decide if you will take TRANXENE while you are pregnant. Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. • If you become pregnant while taking TRANXENE, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can register by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. • Tranxene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take TRANXENE. You and your healthcare provider should decide if you will take TRANXENE or breast feed. You should not do both. 4. Like other antiepileptic drugs, TRANXENE may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop TRANXENE without first talking to a healthcare provider. Stopping TRANXENE suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. What is TRANXENE? TRANXENE is a prescription medicine used: • to treat anxiety disorders • with other medicines to treat partial seizures • to treat the symptoms of sudden alcohol withdrawal Who should not take TRANXENE? Do not take TRANXENE if you: • are allergic to clorazepate dipotassium or any of the ingredients in TRANXENE. See the end of this Medication Guide for a complete list of ingredients in TRANXENE. • have an eye disease called acute narrow angle glaucoma. What should I tell my healthcare provider before taking TRANXENE? Before you take TRANXENE, tell your healthcare provider if you: • have liver or kidney problems • have or have had depression, mood problems, or suicidal thoughts or behavior • have a history of abnormal thinking and behavior (psychotic reactions) • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non prescription medicines, vitamins, and herbal supplements. Taking TRANXENE with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take TRANXENE? • Take TRANXENE exactly as prescribed. Your healthcare provider will tell you how much TRANXENE to take. • Your healthcare provider may change your dose. Do not change your dose of TRANXENE without talking to your healthcare provider. • Do not stop taking TRANXENE without first talking to your healthcare provider. Stopping TRANXENE suddenly can cause serious problems. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If you take too much TRANXENE, call your healthcare provider or local Poison Control Center right away. What are the possible side effects of TRANXENE? See “What is the most important information I should know about TRANXENE?”. The most common side effects of TRANXENE include: • drowsiness • dizziness • upset stomach • blurred vision • dry mouth • confusion These are not all the possible side effects of TRANXENE. For more information ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 800-FDA-1088. How should I store TRANXENE? • Store TRANXENE between 680F to 770F (200C to 250C). • Keep TRANXENE in a tightly closed container. • Keep TRANXENE out of the light. • Keep TRANXENE tablets dry. Keep TRANXENE and all medicines away from children. General Information about TRANXENE Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRANXENE for a condition for which it was not prescribed. Do not give TRANXENE to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about TRANXENE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about TRANXENE that is written for health professionals. For more information about TRANXENE, go to www.lundbeckinc.com or call Lundbeck Inc. at 1 888-514-5204. What are the ingredients in TRANXENE? This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Active ingredient: clorazepate dipotassium Inactive ingredients: colloidal silicon dioxide, magnesium oxide, magnesium stearate, microcrystalline cellulose, potassium carbonate, potassium chloride and talc. In addition: the 3.75 mg tablets contain FD&C Blue No. 2 the 7.5 mg tablets contain FD&C Yellow No. 6 the 15 mg tablets contain FD&C Red No. 3 This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Abbott Pharmaceuticals PR Ltd. Barceloneta, PR 00617 For: Lundbeck Inc. Deerfield, IL 60015, U.S.A. * Trademark of Sanofi-Aventis ® Trademark of Lundbeck Inc. Revised: May 2010 xxx-xxxx This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tranxene label Lundbeck This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tranxene label Lundbeck Lundbeck Inc. 100 Corporate Drive, Suite 104 Lebanon NJ, 08833 908 236 0888 PROGRAM: Adobe Illustrator CS4 for MAC FONTS USED: Helvetica, Stone Sans, Product Name/Description: Tranxene LABEL 7.5 100ct Component Code #: 04-A561-R5 (4390) Date: 04/06/10 Output Scale: 100% Drawing #: Die Size: 3.25 x 1.75” Art Scale: 100% Modified File Date: 05/03/10 Sent to Printer: Rev#: 2 Key Contact: Fisher Creative, LLC. david@davidfishercreative.com 908 534 1964 Avenir, Myriad. OCRB IMPORTED ARTWORK: 2c Lundbeck Logo– 25% black overprints Note: Bar codes are FOR POSITION ONLY. Please replace with Live codes. PMS 179 PMS BLACK PMS 217 PMS 326 VARNISH FREE AREA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lu n dbeck L og o C o l o r B r e a k : 2 - C o l o r P a c k a g i n g Usage Tranxene label This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Appendix A: Proposed REMS NDA 17-105 Tranxene® (clorazepate dipotassium) Tablets Antiepileptic Drug Class Lundbeck, Inc. 4 Parkway North Deerfield, Illinois 60015 Kathryn B. Patterson, Associate Director kpat@lundbeck.com 847-282-5720 RISK EVALUATION AND MITIGATION STRATEGY (REMS) I. GOAL The goal of this REMS is to inform patients about the serious risks associated with the use of Tranxene (clorazepate dipotassium). II. REMS ELEMENTS A. Medication Guide Lundbeck, Inc. will ensure a currently approved Medication Guide will be dispensed with each Tranxene prescription in accordance with 21 CFR 208.24. The currently approved Medication Guide will be included at the end of each package insert and will also be available on Lundbeck’s S.H.A.R.E. website (Support, Help and Resources for Epilepsy) (http://www.lundbeckshare.com/) and Lundbeck’s corporate website (http://www.lundbeck.com/). In accordance with 21 CFR 208.24(d), Lundbeck, Inc. will include a statement on the Tranxene carton/container labels to alert the authorized dispenser to provide a Medication Guide to each patient to whom the drug is dispensed. B. Timetable for Submission of Assessments Lundbeck, Inc will submit REMS Assessments to the FDA 18 months, 3 years and 7 years from the date of approval of the REMS. To facilitate inclusion of as much information as possible while allowing reasonable time to prepare the submission, the reporting interval covered by each assessment should conclude no earlier than 60 days before the submission date for that assessment. Lundbeck, Inc will submit each assessment so it will be received by the FDA on or before the due date. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:09.337020	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017105s076lbl.pdf', 'application_number': 17105, 'submission_type': 'SUPPL ', 'submission_number': 76}
10,973	Page 1 Ultra-TechneKow® DTE (Technetium Tc 99m Generator) Rx Only For the Production of Sodium Pertechnetate To 99m Injection DESCRIPTION: The Ultra-TechneKow® DTE Generator is prepared with fission-produced molybdenum Mo 99 adsorbed onto alumina in a lead shielded column. This generator provides a closed system for the production of sterile metastable technetium Tc 99m, which is produced by the decay of molybdenum Mo 99. Sterile, non-pyrogenic isotonic solutions of Sodium Pertechnetate Tc 99m can be obtained conveniently by periodic aseptic elution of the generator. These solutions should be clear, colorless, and free from any particulate matter. The carrier-free solution may be used as is, or diluted to the proper concentration. Over the life of the generator, an elution will contain an amount of technetium Tc 99m in direct proportion to the quantity of Mo 99 decay since the previous elution of the generator. The exact quantity of Tc 99m in the eluate is determined by column elution efficiency, quantity of Mo 99 on the column, and the elapsed time between elutions. Each eluate of the generator should not contain more than the USP limit of 0.15 kilobecquerel molybdenum Mo 99 per megabecquerel technetium Tc 99m (0.15 microcurie Mo 99 per millicurie Tc 99m) per administered dose at the time of administration and an aluminum ion concentration of not more than 10 micrograms per milliliter of the generator eluate, both of which must be determined by the user before administration. Since the eluate does not contain an antimicrobial agent, it should not be used after 12 hours from the time of generator elution. Physical Characteristics: Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours.1 The principal photon that is useful for detection and imaging studies is listed in Table 1. Table 1. Principal Radiation Emission Data Radiation Mean % Per Disintegration Energy (keV) Gamma-2 89.07 140.5 External Radiation: The specific gamma ray constant for technetium Tc 99m is 0.78 R/hr-mCi at 1 cm. The first half-value layer is 0.017 cm of lead (Pb). A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 2. For example, the use of 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of about 1000. 1 Kocher, David C., "Radioactive Decay Data Tables", DOE/TIC-11026, 108 (1981). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 Table 2. Radiation Attenuation by Lead Shielding Shield Thickness (Pb) cm Coefficient of Attenuation 0.017 0.08 0.16 0.25 0.33 0.5 10-1 10-2 10-3 10-4 Molybdenum Mo 99 decays to technetium Tc 99m with a molybdenum Mo 99 half-life of 2.75 days. The physical decay characteristics of molybdenum Mo 99 are such that only 88.6% of the decaying molybdenum Mo 99 atoms form technetium Tc 99m. Generator elutions may be made at any time, but the amount of technetium Tc 99m available will depend on the interval measured from the last elution. Approximately 47% of the maximum available technetium Tc 99m is reached after 6 hours and 95% after 23 hours. To correct for physical decay of technetium Tc 99m, the fractions that remain at selected intervals of time are shown in Table 3. Table 3. Physical Decay Chart; Technetium Tc 99m, Half Life 6.02 Hours Hours Fraction Remaining Hours Fraction Remaining 0* 1 2 3 4 5 6 1.000 0.891 0.794 0.708 0.631 0.562 0.501 7 8 9 10 11 12 0.447 0.398 0.355 0.316 0.282 0.251 Calibration time. Clinical Pharmacology: The pertechnetate ion distributes in the body similarly to the iodide ion but is not organified when trapped in the thyroid gland. Pertechnetate tends to accumulate in intracranial lesions with excessive neovascularity or an altered blood-brain barrier. It also concentrates in the thyroid gland, salivary glands, stomach and choroid plexus. After intravenous administration it remains in the circulatory system for sufficient time to permit blood pool, organ perfusion, and major vessel studies. It gradually equilibrates with the extracellular space. A fraction is promptly excreted via the kidneys. Following the administration of Sodium Pertechnetate Tc 99m as an eye drop, the drug mixes with tears within the conjunctival space. Within seconds to minutes it leaves the conjunctival space and escapes into the inferior meatus of the nose through the nasolacrimal drainage system. During this process the pertechnetate ion passes through the canaliculi, the lacrimal sac and the nasolacrimal duct. In the event of any anatomical or functional blockage of the drainage system there will be a backflow resulting in tearing (epiphora). Thus the pertechnetate escapes the conjunctival space in the tears. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 While the major part of the pertechnetate escapes within a few minutes of normal drainage and tearing, it has been documented that there is some degree of transconjunctival absorption with turnover of 1.5% per minute in normal individuals, 2.1 % per minute in patients without any sac and 2.7% per minute in patients with inflammed conjunctiva due to chronic dacryocystitis. Individual values may vary but these rates are probably representative and indicate that the maximum possible pertechnetate absorbed will remain below one thousandth of that used in other routine diagnostic procedures. INDICATIONS AND USAGE: Sodium Pertechnetate Tc 99m is used IN ADULTS as an agent for: Brain Imaging (including cerebral radionuclide angiography) Thyroid Imaging Salivary Gland Imaging Placenta Localization Blood Pool Imaging (including radionuclide angiography) Urinary Bladder Imaging (direct isotopic cystography) for detection of vesico-ureteral reflux Nasolacrimal Drainage System Imaging (dacryoscintigraphy) Sodium Pertechnetate Tc 99m is used IN PEDIATRIC PATIENTS as an agent for: Brain Imaging (including cerebral radionuclide angiography) Thyroid Imaging Blood Pool Imaging (including radionuclide angiography) Urinary Bladder Imaging (direct isotopic cystography) for the detection of vesico-ureteral reflux CONTRAINDICATIONS: None known. WARNINGS: Radiation risks associated with the use of Sodium Pertechnetate Tc 99m are greater in pediatric patients than in adults and, in general, the younger the patient the greater the risk owing to greater absorbed radiation doses and longer life expectancy. These greater risks should be taken firmly into account in all benefit risk assessments involving pediatric patients. Only use generator eluant specified for use with the Ultra-TechneKow® DTE Generator. Do not use any other generator eluant or saline from any other source. PRECAUTIONS: As in the use of any radioactive material, care should be taken to minimize radiation exposure to the patient consistent with proper patient management and to insure minimum radiation exposure to occupational workers. Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 After the termination of the nasolacrimal imaging procedure, blowing the nose and washing the eyes with sterile distilled water or an isotonic sodium chloride solution will further minimize the radiation dose. Since the eluate does not contain an antimicrobial agent, it should not be used after 12 hours from time of generator elution. Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to evaluate carcinogenic or mutagenic potential or whether Sodium Pertechnetate Tc 99m may affect fertility in males or females. Pregnancy Category C: Animal reproductive studies have not been conducted with Sodium Pertechnetate Tc 99m. It is also not known whether Sodium Pertechnetate Tc 99m can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Sodium Pertechnetate Tc 99m should be given to pregnant women only if the expected benefits to be gained clearly outweigh the potential hazards. Ideally, examinations using radiopharmaceutical drug products - especially those elective in nature - of women of childbearing capability should be performed during the first ten days following the onset of menses. Nursing Mothers: Technetium Tc 99m is excreted in human milk during lactation, therefore, formula-feedings should be substituted for breast-feedings. Pediatric Use: See Indications and Usage and Dosage and Administration sections. Also see the description of additional risk under Warnings. ADVERSE REACTIONS: Allergic reactions including anaphylaxis have been reported infrequently following the administration of Sodium Pertechnetate Tc 99m. DOSAGE AND ADMINISTRATION: Sodium Pertechnetate Tc 99m is usually administered by intravenous injection, but can be given orally. When imaging the nasolacrimal drainage system, instill the Sodium Pertechnetate Tc 99m by the use of a device such as a micropipette or similar method which will ensure the accuracy of the dose. For imaging the urinary bladder and ureters (direct isotopic cystography), the Sodium Pertechnetate Tc 99m is administered by direct instillation aseptically into the bladder via a urethral catheter, following which the catheter is flushed with approximately 200 mL of sterile saline directly into the bladder. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 The dosage employed varies with each diagnostic procedure. If the oral route is elected, the patient should fast for at least six (6) hours before and two (2) hours after administration. The suggested dose ranges employed for various diagnostic indications in the average ADULT PATIENT (70 kg) are as follows: Vesico-ureteral imaging: 18.5 to 37 MBq (0.5 to 1 mCi) Brain imaging: 370 to 740 MBq (10 to 20 mCi) Thyroid gland imaging: 37 to 370 MBq (1 to 10 mCi) Salivary gland imaging: 37 to 185 MBq (1 to 5 mCi) Placenta localization: 37 to 111 MBq (1 to 3 mCi) Blood pool imaging: 370 to 1110 MBq (10 to 30 mCi) Nasolacrimal drainage system: Maximum dose of 3.7 MBq (100µCi) The recommended dosages in PEDIATRIC PATIENTS are: Vesico-ureteral imaging: 18.5 to 37 MBq (0.5 to 1 mCi) Brain imaging: 5.18 to 10.36 MBq (140 to 280 µCi) per kg body weight Thyroid gland imaging: 2.22 to 2.96 MBq (60 to 80 µCi) per kg body weight Blood pool imaging: 5.18 to 10.36 MBq (140 to 280 µCi) per kg body weight Minimum dose of 111 to 185 MBq (3 to 5 mCi) should be employed if radionuclide angiography is performed as part of the brain imaging or blood pool imaging procedures. NOTE: Up to 1 gram of pharmaceutical grade potassium perchlorate in a suitable base or capsule may be given orally prior to administration of Sodium Pertechnetate Tc 99m for brain imaging, placenta localization and blood pool imaging. When Sodium Pertechnetate Tc 99m is used in pediatric patients for brain or blood pool imaging, administration of potassium perchlorate is especially important to minimize the absorbed radiation dose to the thyroid gland. The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution to be administered as the patient dose should be clear, colorless, and contain no particulate matter. Radiation Dosimetry: The estimated absorbed radiation doses2 to an average ADULT patient (70 kg) from an intravenous injection of a maximum dose of 1110 megabecquerels (30 millicuries) of Sodium Pertechnetate Tc 99m distributed uniformly in the total body of subjects not pretreated with blocking agents, such as pharmaceutical grade potassium perchlorate, are shown in Table 4. For placental localization studies, when a maximum dose of 111 megabecquerels (3 millicuries) is used, it is assumed to be uniformly equilibrated between maternal and fetal tissues. 2 Modified from: Summary of Current Radiation Dose Estimates to Normal Humans from Tc 99m as Sodium Pertechnetate. MIRD Dose Estimate Report No. 8. J. Nucl. Med., 17 (1): 74-7, 1976. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 The estimated absorbed radiation doses to an ADULT patient from the nasolacrimal imaging procedure using a maximum dose of 3.7 megabecquerels (100 microcuries) of Sodium Pertechnetate Tc 99m are shown in Table 5. Table 4. Absorbed Radiation Doses From Intravenous Injection (ADULTS) 1110 MBq (30 mCi) Dose Resting Population Active Population 111 MBq (3mCi) Dose Tissue mGy rads mGy rads mGy rads Bladder Wall Gastrointestinal tract: Stomach wall Upper large intestine wall Lower large intestine wall Red Marrow Testes Ovaries Thyroid Brain Total Body Placenta Fetus 15.9 75.0 20.4 18.3 5.7 2.7 6.6 39.0 4.2 4.2 1.59 7.50 2.04 1.83 0.57 0.27 0.66 3.90 0.42 0.42 25.5 15.3 36.0 33.0 5.1 2.7 9.0 39.0 3.6 3.3 2.55 1.53 3.60 3.30 0.51 0.27 0.90 3.90 0.36 0.33 0.5 0.5 0.05 0.05 Table 5. Absorbed Radiation Doses from Dacryoscintigraphy 3.7 MBq (100 µCi) Dose of Sodium Pertechnetate Tc 99m Tissue mGys rads Eye Lens: If lacrimal fluid turnover is 16%/min If lacrimal fluid turnover is 100%/min If drainage system is blocked Total Body Ovaries* Testes* Thyroid* 0.140 0.022 4.020 0.011 0.030 0.009 0.130 0.014 0.002 0.402 0.001 0.003 0.001 0.013 *Assuming no blockage of draining system. MIRD Dose Estimate Report No. 8, J Nucl. Med., 17: 74-77,1976 In PEDIATRIC patients, the maximum radiation doses when a dose of 185 megabecquerels (5 millicuries) Sodium Pertechnetate Tc 99m is administered to a neonate (3.5 kg) for brain or blood pool imaging with radionuclide angiography are shown in Table 6. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 In pediatric patients, an average 30 minute exposure to 37 megabecquerels (1 millicurie) of Sodium Pertechnetate Tc 99m following instillation for direct cystography, results in an estimated absorbed radiation dose of approximately 300 micrograys (30 millirads) to the bladder wall and 40 to 50 micrograys (4 to 5 millirads) to the gonads.3 Table 6. Absorbed Radiation Doses From Intravenous Injection (PEDIATRIC) 37 MBq (1 mCi) Dose 185 MBq (5mCi) Dose Tissue mGys rads mGys rads Thyroid (without perchlorate) Thyroid (with perchlorate) Large Bowel (with perchlorate) Testes Ovaries Total Body 46.0 9.7 19.0 1.0 2.2 1.5 4.60 0.97 1.90 0.10 0.22 0.15 230.0 48.5 95.5 5.1 11.0 7.6 23.0 4.85 9.55 0.51 1.10 0.76 HOW SUPPLIED: The Ultra-TechneKow DTE (Technetium Tc 99m) Generators contain the following amount of molybdenum Mo 99 at the date and time of calibration stated on the label. Catalog No. 881 18.5 gigabecquerels (0.50 curie) NDC 0019-9881-01 882 27.75 gigabecquerels (0.75 curie) NDC 0019-9882-02 883 37 gigabecquerels (1.0 curie) NDC 0019-9883-03 884 55.5 gigabecquerels (1.5 curies) NDC 0019-9884-04 885 74 gigabecquerels (2.0 curies) NDC 0019-9885-05 886 92.5 gigabecquerels (2.5 curies) NDC 0019-9886-06 887 111 gigabecquerels (3.0 curies) NDC 0019-9887-07 888 129.5 gigabecquerels (3.5 curie) NDC 0019-9888-08 889 185 gigabecquerels (5.0 curie) NDC 0019-9889-09 890 222 gigabecquerels (6.0 curie) NDC 0019-9890-10 891 277.5 gigabecquerels (7.5 curie) NDC 0019-9891-11 892 407 gigabecquerels (11.0 curie) NDC 0019-9892-12 893 518 gigabecquerels (14.0 curie) NDC 0019-9893-13 894 592 gigabecquerels (16.0 curie) NDC 0019-9894-14 895 703 gigabecquerels (19.0 curie) NDC 0019-9895-15 3 Conway, J.J., et al., Direct and indirect radionuclide cystography. J. Urol. 113:689-693, May 1975. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 Each generator is supplied with the following components for the elution of the generator 7 - Evacuated Collecting Vials, 10 mL, Sterile, Non-pyrogenic or 5 - Evacuated Collecting Vials, 20 mL, Sterile, Non-Pyrogenic 7 - 70% (v/v) Isopropyl Alcohol Wipes 7 - Pressure-sensitive "Caution - Radioactive Material" collecting vial labels 7 - Pressure-sensitive radioassay data labels for lead elution shield 1 - Generator Eluant Vial, 135 mL, Sterile, Non-Pyrogenic 1 - TechneStatTM Vial, 5mL, containing 0.5 mL of 1.5 mg/mL methylparaben and 0.2 mg/mL propylparaben 1- Package Insert The sterile, non-pyrogenic solution used to elute the generator column contains 0.9% sodium chloride. The eluant does not contain an antimicrobial agent. EVACUATED COLLECTING VIALS. Collecting vials are available on request in 10 and 20 milliliter sizes. Storage: Store generator and Sodium Pertechnetate Tc 99m solution at controlled room temperature 20- 25°C (68-77°F). Expiration Date: The generator should not be used after the expiration date stated on the label. The expiration time of the Sodium Pertechnetate Tc 99m solution is not later than 12 hours after time of elution. If the eluate is used to reconstitute a kit, the radiolabeled kit should not be used after 12 hours from the time of generator elution or after the expiration time stated on the labeling for the prepared drug, whichever is earlier. Directions for Use of the Technetium Tc 99m Generator: NOTE 1: Immediately upon delivery, the generator should be placed within a minimum of one- inch of lead shielding in such a manner so as to minimize radiation exposure to attending personnel. NOTE 2: Wear waterproof gloves during the elution procedure and during subsequent reconstitution of kits with the eluate. NOTE 3: Use a shielded syringe to withdraw patient dose or to transfer Sodium Pertechnetate Tc 99m into mixing vials during kit reconstitution. NOTE 4: The needles in the generator are sterile beneath their covers, and the generator has been cleaned underneath the top cover. Additional disinfection of these areas with agents containing alcohol may unfavorably influence the Tc 99m yield. Eluting the generator every 24 hours will provide optimal amounts of Sodium Pertechnetate Tc 99m. However, the generator may be eluted whenever sufficient amounts of technetium Tc 99m have accumulated within the column. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 For Example: Time After Approximate Yield First Elution (hrs.) (% of First Elution) 1 10 2 19 3 27 4 35 5 41 6 47 Preparation: 1. Rotate the top cover 30° counterclockwise and lift up to remove. 2. Lift generator by its handle and position inside the auxiliary shield, aligning the notch in the elution station with leaded glass window in the auxiliary shield. 3. Remove the flip-top cap of the eluant vial, disinfect the stopper, remove and store the needle cover over the eluant needles, invert the eluant vial and push down into place on the eluant needles. 4. Remove the flip-top cap of the TechneStat vial and place it into the TechneStat vial shield. 5. Remove and store the needle cover from the elution station, replace the lid of the auxiliary shield and insert the shielded TechneStat vial into the elution station. Elution: 1. Remove the flip-top cap of the appropriate evacuated vial, disinfect the stopper, and put the vial into the elution shield aligning the volume scale on the evacuated vial with the leaded glass window. 2. Replace the shielded TechneStat vial with the shielded evacuated vial, aligning the two leaded glass windows. Piercing the septum of the evacuated vial with the elution needle will begin the elution process. 3. Wait until the evacuated vial has completely filled itself (a few minutes). Never interrupt the elution by lifting the vial shielding! NOTE: Do not use generator eluate if its appearance is discolored. 4. Replace the shielded vial with the shielded TechneStat vial. 5. Determine the technetium Tc 99m concentration and molybdenum Mo 99 content for dispensing purposes. NOTE: Molybdenum Mo 99 breakthrough Limit - The acceptable limit is 0.15 kilobecquerel molybdenum Mo 99 per megabecquerel technetium Tc 99m (0.15 microcurie Mo 99 per millicurie Tc 99m) at the time of administration. 6. Determine the aluminum ion concentration of the eluate. NOTE: Aluminum Ion breakthrough Limit - The acceptable limit is not more than 10 micrograms per milliliter of eluate. Subsequent Elutions: Repeat steps 1 through 6 of the Elution procedure above. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 Vacuum Loss: If the vacuum in the collecting vial is lost, do not attempt to re-evacuate the vial, but discard and use a new collecting vial. EXPIRED GENERATOR DISPOSAL: 1. Following the life of the generator, remove and dispose of the used TechneStat vial and the eluant vial. 2. Cover the inlet and outlet needles with the stored needle covers. 3. Close the generator system with its top cover by rotating with downward pressure. 4. The intact generator assembly should be either returned to Mallinckrodt Inc. or disposed of in accordance with applicable regulations. This generator is approved for use by persons licensed by the U.S. Nuclear Regulatory Commission to use by-product material identified in Section 35.200 or under equivalent licenses of Agreement States. Revised 6/2001 Mallinckrodt Inc. St. Louis, MO 63134 MALLINCKRODT 880-887 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:09.388206	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/17243s025lbl.pdf', 'application_number': 17243, 'submission_type': 'SUPPL ', 'submission_number': 25}
10,972	CIV DARVOCET-N® 50 and DARVOCET-N® 100 (PROPOXYPHENE NAPSYLATE AND ACETAMINOPHEN TABLETS, USP) Rx only WARNINGS • There have been numerous cases of accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol. Fatalities within the first hour of overdosage are not uncommon. Many of the propoxyphene related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation. • The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. Patients receiving propoxyphene and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see CLINICAL PHARMACOLOGY – Drug Interactions, and WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION for further information). DESCRIPTION Darvocet-N contains propoxyphene napsylate and acetaminophen. Propoxyphene Napsylate, USP is an odorless, white crystalline powder with a bitter taste. It is very slightly soluble in water and soluble in methanol, ethanol, chloroform, and acetone. Chemically, it is (αS,1R)-α-[2-(Dimethylamino)-1-methylethyl]-α phenylphenethyl propionate compound with 2-naphthalenesulfonic acid (1:1) monohydrate, which can be represented by the accompanying structural formula. Its molecular weight is 565.72. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Structural Formula Propoxyphene napsylate differs from propoxyphene hydrochloride in that it allows more stable liquid dosage forms and tablet formulations. Because of differences in molecular weight, a dose of 100 mg (176.8 μmol) of propoxyphene napsylate is required to supply an amount of propoxyphene equivalent to that present in 65 mg (172.9 μmol) of propoxyphene hydrochloride. Acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste. The molecular formula for acetaminophen is C8H9NO2 and the molecular Structural Formula Each tablet of Darvocet-N 50 contains 50 mg (88.4 μmol) propoxyphene napsylate and 325 mg (2,150 μmol) acetaminophen. Each tablet of Darvocet-N 100 contains 100 mg (176.8 μmol) propoxyphene napsylate and 650 mg (4,300 μmol) acetaminophen. Each tablet also contains amberlite, cellulose, F D & C Yellow No. 6, magnesium stearate, stearic acid, titanium dioxide, and other inactive ingredients. CLINICAL PHARMACOLOGY Pharmacology Propoxyphene is a centrally acting opiate analgesic. In vitro studies demonstrated propoxyphene and the metabolite norpropoxyphene inhibit sodium channels (local anesthetic effect) with norpropoxyphene being approximately 2-fold more potent than propoxyphene and propoxyphene approximately 10-fold more potent than lidocaine. Propoxyphene and norpropoxyphene inhibit the voltage-gated potassium current carried by cardiac rapidly activating delayed rectifier (hERG) channels with approximately equal potency. It is unclear if the effects on ion channels occur within therapeutic dose range. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Acetaminophen is a non-opiate, non-salicylate analgesic and antipyretic. The site and mechanism for the analgesic effect of acetaminophen has not been determined. The antipyretic effect of acetaminophen is mediated through activity in the hypothalamic heat-regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing. Pharmacokinetics Absorption Peak plasma concentrations of propoxyphene are reached in 2 to 2.5 h. After a 65-mg oral dose of propoxyphene hydrochloride, peak plasma levels of 0.05 to 0.1 μg/mL for propoxyphene and 0.1 to 0.2 μg/mL for norpropoxyphene (major metabolite) are achieved. Repeated doses of propoxyphene at 6 h intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 h. Propoxyphene has a half-life of 6 to 12 h, whereas that of norpropoxyphene is 30 to 36 h. Acetaminophen is absorbed from the gastrointestinal tract and has a plasma half-life of 1.25 to 3 h, which may be increased by liver damage and following overdosage. Distribution Propoxyphene is about 80% bound to proteins and has a large volume of distribution, 16 L/kg. Acetaminophen is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; only 20% to 50% may be bound at the concentrations encountered during acute intoxication. Metabolism Propoxyphene undergoes extensive first-pass metabolism by intestinal and hepatic enzymes. The major route of metabolism is cytochrome CYP3A4 mediated N demethylation to norpropoxyphene, which is excreted by the kidneys. Ring hydroxylation and glucuronide formation are minor metabolic pathways. Acetaminophen is extensively metabolized in the liver. Less than 5% of acetaminophen dose is excreted unchanged in the kidney. About 85% of an acetaminophen dose is metabolized by conjugation, mainly glucuronidation via UDP-glucuronosyltransferase (mainly UGT1A6) and to a lesser extent sulfation via sulfotransferase (mainly SLT1A1 and SLT1A3). The glucuronide and sulfate conjugates are nontoxic and are largely excreted in the urine and bile. About 8-10% of an acetaminophen dose is oxidized by cytochrome CYP2E1 to form the toxic reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is further metabolized via glutathione (GSH) conjugation, yielding non-toxic thiol metabolites including cysteine, mercapturate, methylthioacetaminophen, and methanesulfinylacetaminophen that are excreted in the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda urine. Acetaminophen is also oxidized at a low percentage by cytochrome CYP2A6 to form inert catechols (e.g., methoxyacetaminophen). Excretion In 48 h, approximately 20 to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene. The renal clearance rate of propoxyphene is 2.6 L/min. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. SPECIAL POPULATIONS Geriatric Patients After oral administration of propoxyphene in elderly patients (70-78 years), much longer half-lives of propoxyphene and norpropoxyphene have been reported (propropoxyphene 13 to 35 h, norpropoxyphene 22 to 41 h). In addition, the AUC was an average of 3-fold higher and the Cmax was an average of 2.5-fold higher in the elderly when compared to a younger (20-28 years) population. Longer dosage intervals may be considered in the elderly because the metabolism of propoxyphene may be reduced in this patient population. After multiple oral doses of propoxyphene in elderly patients (70-78 years), the Cmax of the metabolite (norpropoxyphene) was increased 5-fold. Pediatric Patients Neither propoxyphene alone nor in combination with acetaminophen has been studied in pediatric patients. Hepatic Impairment No formal pharmacokinetic study of either propoxyphene alone or in combination with acetaminophen has been conducted in patients with mild, moderate or severe hepatic impairment. After oral administration of propoxyphene in patients with cirrhosis, plasma concentrations of propoxyphene were considerably higher and norpropoxyphene concentrations were much lower than in control patients. This is presumably because of a decreased first-pass metabolism of orally administered propoxyphene in these patients. The AUC ratio of norpropoxyphene: propoxyphene was significantly lower in patients with cirrhosis (0.5 to 0.9) than in controls (2.5 to 4). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Compared to healthy subjects, acetaminophen had a lower total clearance and longer half-life in patients with liver disease. Decreased metabolite formation clearance (8-42 %) was observed in subjects with liver disease compared to healthy subjects after both single and multiple-doses (at steady state). In addition, there is an increase in the amount of acetaminophen excreted unchanged in the urine (4.7% vs. 2.5%) in patients with liver disease compared to healthy subjects after repeat doses, suggesting that more acetaminophen was excreted by renal elimination in the liver disease state. Renal Impairment No formal pharmacokinetic study of either propoxyphene alone or in combination with acetaminophen has been conducted in patients with mild, moderate or severe renal impairment. After oral administration of propoxyphene in anephric patients, the AUC and Cmax values were an average of 76% and 88% greater, respectively. Dialysis removes only insignificant amounts (8%) of administered dose of propoxyphene. Drug Interactions The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. On the other hand, strong CYP3A4 inducers such as rifampin may lead to enhanced metabolite (norpropoxyphene) levels. Propoxyphene is also thought to possess CYP3A4 and CYP2D6 enzyme inhibiting properties. Coadministration with a drug that is a substrate of CYP3A4 or CYP2D6, may result in higher plasma concentrations and increased pharmacologic or adverse effects of that drug. CLINICAL STUDIES The efficacy of propoxyphene in combination with acetaminophen was studied in seven single-dose, randomized, double-blind, placebo-controlled trials in patients with mild to severe postpartum pain. One of the studies demonstrated that both propoxyphene and acetaminophen in the combination contributed to a greater reduction in pain than acetaminophen and propoxyphene alone and that propoxyphene was superior to placebo. There is insufficient information available to assess efficacy of propoxyphene in combination with acetaminophen in patients with chronic pain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATION Darvocet-N is indicated for the relief of mild to moderate pain. CONTRAINDICATIONS Darvocet-N is contraindicated in patients with known hypersensitivity to propoxyphene or acetaminophen. Darvocet-N is contraindicated in patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe asthma or hypercarbia. Darvocet-N is contraindicated in any patient who has or is suspected of having paralytic ileus. WARNINGS Risk of Overdose There have been numerous cases of accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol. Fatalities within the first hour of overdosage are not uncommon. Many of the propoxyphene-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation. Respiratory Depression Respiratory depression is the chief hazard from all opioid agonist preparations. Respiratory depression occurs most frequently in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration. Darvocet-N should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of Darvocet-N may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. Hypotensive Effect This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Darvocet-N, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Darvocet-N may produce orthostatic hypotension in ambulatory patients. Darvocet-N, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Drug Interactions The concomitant use of propoxyphene and CNS depressants, including alcohol, can result in potentially serious adverse events including death. Because of its added depressant effects, propoxyphene should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Usage in Ambulatory Patients Propoxyphene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly. Use with Other Acetaminophen-Containing Agents Due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose, Darvocet-N should not be used concomitantly with other acetaminophen-containing products. Use with Alcohol Hepatotoxicity and severe hepatic failure occurred in chronic alcoholics following therapeutic doses of acetaminophen. Patients should be cautioned about the concomitant use of propoxyphene products and alcohol because of potentially serious CNS-additive effects of these agents that can lead to death. PRECAUTIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tolerance and Physical Dependence Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy). If Darvocet-N is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur (see DRUG ABUSE AND DEPENDENCE). If signs and symptoms of withdrawal occur, patients should be treated by reinstitution of opioid therapy followed by gradual tapered dose reduction of Darvocet-N combined with symptomatic support (see DOSAGE AND ADMINISTRATION: Cessation of Therapy). Use in Pancreatic/Biliary Tract Disease Darvocet-N may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like Darvocet- N may cause increases in the serum amylase level. Hepatic or Renal Impairment Insufficient information exists to make appropriate dosing recommendations regarding the use of either propoxyphene alone or in combination with acetaminophen in patients with hepatic or renal impairment as a function of degree of impairment. Higher plasma concentrations and/or delayed elimination may occur in case of impaired hepatic function and/or impaired renal function (see CLINICAL PHARMACOLOGY). If the drug is used in these patients, it should be used with caution because of the hepatic metabolism of propoxyphene and acetaminophen and renal excretion of their metabolites. Information for Patients/Caregivers 1. Patients should be advised to report pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Patients should be advised not to adjust the dose of Darvocet-N without consulting the prescribing professional. 3. Patients should be advised that Darvocet-N may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). 4. Patients should not combine Darvocet-N with central nervous system depressants (e.g., sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur. 5. Patients should be instructed not to consume alcoholic beverages, including prescription and over-the-counter medications that contain alcohol, while using Darvocet-N because of risk of serious adverse events including death. 6. Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child. 7. Patients should be advised that Darvocet-N is a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. 8. Patients should be advised that if they have been receiving treatment with Darvocet- N for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the Darvocet-N dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication. 9. Instruct patients not to consume any other medication that contain acetaminophen, including acetaminophen-based over-the-counter medications, while taking Darvocet-N. Drug Interactions with Propoxyphene Propoxyphene is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when propoxyphene is administered concurrently with agents that affect CYP3A4 activity. The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. Coadministration with agents that induce CYP3A4 activity may reduce the efficacy of propoxyphene. Strong CYP3A4 inducers such as rifampin may lead to enhanced metabolite (norpropoxyphene) levels. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Propoxyphene is also thought to possess CYP3A4 and CYP2D6 enzyme inhibiting properties and coadministration with drugs that rely on either of these enzymes for metabolism may result in increased pharmacologic or adverse effects of that drug. Severe neurologic signs, including coma, have occurred with concurrent use of carbamazepine (metabolized by CYP3A4). Increased risk of bleeding has been observed with warfarin-like agents when given along with propoxyphene; however, the mechanistic basis of this interaction is unknown. CNS Depressants Patients receiving narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with Darvocet-N may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dosage of Darvocet-N. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as Darvocet-N. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of Darvocet-N and/or may precipitate withdrawal symptoms in these patients. Monoamine Oxidase Inhibitors (MAOIs) MAOIs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant depression of respiration or coma. The use of Darvocet-N is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Drug Interactions with Acetaminophen Alcohol: Hepatotoxicity has occurred in chronic alcoholics following various dose levels (moderate to excessive) of acetaminophen. Anticholinergics: The onset of acetaminophen effect may be delayed or decreased slightly, but the ultimate pharmacological effect is not significantly affected by anticholinergics. Oral Contraceptives: Increase in glucuronidation resulting in increased plasma clearance and a decreased half-life of acetaminophen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Beta Blockers (Propranolol): Propranolol appears to inhibit the enzyme systems responsible for the glucuronidation and oxidation of acetaminophen. Therefore, the pharmacologic effects of acetaminophen may be increased. Loop Diuretics: The effects of the loop diuretic may be decreased because acetaminophen may decrease renal prostaglandin excretion and decrease plasma renin activity. Lamotrigine: Serum lamotrigine concentrations may be reduced, producing a decrease in therapeutic effects. Probenecid: Probenecid may increase the therapeutic effectiveness of acetaminophen slightly. Zidovudine: The pharmacologic effects of zidovudine may be decreased because of enhanced nonhepatic or renal clearance of zidovudine. Carcinogenesis, Mutagenesis, Impairment of Fertility The mutagenic and carcinogenic potential of propoxyphene and acetaminophen alone and in combination have not been evaluated. In animal studies there was no effect of propoxyphene on mating behavior, fertility, duration of gestation, or parturition when rats were fed propoxyphene as a component of their daily diet at estimated daily propoxyphene intake up to 8-fold greater than the maximum human equivalent dose (HED) based on body surface area comparison. At this highest dose, fetal weight and survival on postnatal day 4 was reduced. Acetaminophen has not been studied in animals for effects on fertility and the effects on human fertility are unknown. Pregnancy Risk summary Pregnancy category C. There are no adequate and well-controlled studies of propoxyphene with acetaminophen in pregnant women. While there are limited data in the published literature, adequate animal reproduction studies have not been conducted with propoxyphene or acetaminophen. Therefore, it is not known whether propoxyphene or acetaminophen can affect reproduction or cause fetal harm when administered to a pregnant woman. Propoxyphene with acetaminophen should be given to a pregnant woman only if clearly needed. Clinical considerations Acetaminophen, propoxyphene and its major metabolite, norpropoxyphene, cross the human placenta. Neonates whose mothers have taken opiates chronically may exhibit respiratory depression or withdrawal symptoms. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Data In published animal reproduction studies, no teratogenic effects occurred in offspring born to pregnant rats or rabbits that received propoxyphene during organogenesis. Pregnant animals received propoxyphene doses approximately 10-fold (rats) and 4-fold (rabbits) the maximum recommended human dose (based on mg/m2 body surface area comparison). Nursing Mothers Propoxyphene, norpropoxyphene (major metabolite), and acetaminophen are excreted in human milk. Published studies of nursing mothers using propoxyphene detected no adverse effects in nursing infants. Based on a study of six mother-infant pairs, an exclusively breastfed infant receives approximately 2% of the maternal weight-adjusted dose. Norpropoxyphene is renally excreted and renal clearance is lower in neonates than in adults. Therefore, it is possible that prolonged maternal propoxyphene use could result in norpropoxyphene accumulation in a breastfed infant. Watch breastfeeding infants for signs of sedation including poor feeding, somnolence, or respiratory depression. Caution should be exercised when Darvocet-N is administered to a nursing woman. Pediatric Patients Safety and effectiveness in pediatric patients have not been established. Elderly Patients Clinical studies of Darvocet-N did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, postmarketing reports suggest that patients over the age of 65 may be more susceptible to CNS-related side effects. Therefore, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Decreased total daily dosage should be considered (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS During clinical trials, the most frequently reported adverse reactions were dizziness, sedation, nausea, and vomiting. Other adverse reactions include constipation, abdominal pain, skin rashes, lightheadedness, headache, weakness, euphoria, dysphoria, hallucinations, and minor visual disturbances. The most frequently reported postmarketing adverse events have included completed suicide, accidental and intentional overdose, drug dependence, cardiac arrest, coma, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drug ineffective, drug toxicity, nausea, respiratory arrest, cardio-respiratory arrest, death, vomiting, dizziness, convulsion, confusional state, and diarrhea. Additional adverse experiences reported through postmarketing surveillance include: Cardiac disorders: arrhythmia, bradycardia, cardiac/respiratory arrest, congestive arrest, congestive heart failure (CHF), tachycardia, myocardial infarction (MI) Eye disorder: eye swelling, vision blurred General disorder and administration site conditions: drug ineffective, drug interaction, drug tolerance, influenza type illness, drug withdrawal syndrome Gastrointestinal disorder: gastrointestinal bleed, acute pancreatitis Hepatobiliary disorder: hepatic steatosis, hepatomegaly, hepatocellular injury Immune system disorder: hypersensitivity Injury poisoning and procedural complications: drug toxicity, hip fracture, multiple drug overdose, narcotic overdose Investigations: blood pressure decreased, heart rate elevated/abnormal Metabolism and nutrition disorder: metabolic acidosis Nervous system disorder: ataxia, coma, dizziness, somnolence, syncope Psychiatric: abnormal behavior, confusional state, hallucinations, mental status change Respiratory, thoracic, and mediastinal disorders: respiratory depression, dyspnoea Skin and subcutaneous tissue disorder: rash, itch Liver dysfunction has been reported in association with both active components of Darvocet-N 50 and Darvocet-N 100. Propoxyphene therapy has been associated with abnormal liver function tests and, more rarely, with instances of reversible jaundice (including cholestatic jaundice). Hepatic necrosis may result from acute overdose of acetaminophen (see OVERDOSAGE). In chronic ethanol abusers, this has been reported rarely with short-term use of acetaminophen dosages of 2.5 to 10 g/day. Fatalities have occurred. There have also been postmarketing reports of renal papillary necrosis associated with chronic acetaminophen use, particularly when the dosage is greater than recommended and when combined with aspirin. Subacute painful myopathy has been reported following chronic propoxyphene overdosage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DRUG ABUSE AND DEPENDENCE Controlled Substance Darvocet-N is a Schedule IV narcotic under the U.S. Controlled Substances Act. Darvocet-N can produce drug dependence of the morphine type, and therefore, has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration. Darvocet-N should be prescribed and administered with the same degree of caution appropriate to the use of other narcotic- containing medications. Abuse Since Darvocet-N is a mu-opioid agonist, it may be subject to misuse, abuse, and addiction. Addiction to opioids prescribed for pain management has not been estimated. However, requests for opioids from opioid-addicted patients occur. As such, physicians should take appropriate care in prescribing Darvocet-N. Dependence Opioid analgesics may cause psychological and physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug after long term administration. Also, symptoms of withdrawal may be precipitated through the administration of drugs with mu-opioid antagonist activity, e.g., naloxone or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine, dezocine) (see OVERDOSAGE). Physical dependence usually does not occur to a clinically significant degree, until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required to produce the same degree of analgesia, is initially manifested by a shortened duration of an analgesic effect and subsequently, by decreases in the intensity of analgesia. In chronic pain patients, and in opioid-tolerant cancer patients, the administration of Darvocet-N should be guided by the degree of tolerance manifested and the doses needed to adequately relieve pain. The severity of the Darvocet-N abstinence syndrome may depend on the degree of physical dependence. Withdrawal is characterized by rhinitis, myalgia, abdominal cramping, and occasional diarrhea. Most observable symptoms disappear in 5 to 14 days without treatment; however, there may be a phase of secondary or chronic abstinence which may last for 2 to 6 months characterized by insomnia, irritability, and muscular aches. The patient may be detoxified by gradual reduction of the dose. Gastrointestinal disturbances or dehydration should be treated with supportive care. OVERDOSAGE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Darvocet-N is a combination product containing propoxyphene and acetaminophen. Overdose of Darvocet-N may present with the signs and symptoms of propoxyphene overdose, acetaminophen overdose or both. Fatalities within the first hour of overdosage are not uncommon. In all cases of suspected overdosage, call your regional Poison Control Center to obtain the most up-to-date information about the treatment of overdose. This recommendation is made because, in general, information regarding the treatment of overdosage may change more rapidly than do package inserts. Initial consideration should be given to the management of the CNS effects of propoxyphene overdosage. Resuscitative measures should be initiated promptly. Propoxyphene Overdosage Symptoms of Propoxyphene Overdosage The manifestations of acute overdosage with propoxyphene are those of opioid overdosage. The patient is usually somnolent but may be stuporous or comatose and convulsing. Respiratory depression is characteristic. The ventilatory rate and/or tidal volume is decreased, which results in cyanosis and hypoxia. Pupils, initially pinpoint, may become dilated as hypoxia increases. Cheyne-Stokes respiration and apnea may occur. Blood pressure and heart rate are usually normal initially, but blood pressure falls and cardiac performance deteriorates, which ultimately results in pulmonary edema and circulatory collapse, unless the respiratory depression is corrected and adequate ventilation is restored promptly. Cardiac arrhythmias and conduction delay may be present. A combined respiratory-metabolic acidosis occurs owing to retained CO2 (hypercapnia) and to lactic acid formed during anaerobic glycolysis. Acidosis may be severe if large amounts of salicylates have also been ingested. Death may occur. Treatment of Propoxyphene Overdosage Attention should be directed first to establishing a patent airway and to restoring ventilation. Mechanically assisted ventilation, with or without oxygen, may be required, and positive pressure respiration may be desirable if pulmonary edema is present. The opioid antagonist naloxone will markedly reduce the degree of respiratory depression, and should be administered promptly, preferably intravenously. The duration of action of the antagonist may be brief. If no response is observed after 10 mg of naloxone have been administered, the diagnosis of propoxyphene toxicity should be questioned. In addition to the use of an opioid antagonist, the patient may require careful titration with an anticonvulsant to control convulsions. Activated charcoal can adsorb a significant amount of ingested propoxyphene. Dialysis is of little value in poisoning due to propoxyphene. Efforts should be made to determine whether other agents, such as alcohol, barbiturates, tranquilizers, or other CNS depressants, were also ingested, since these increase CNS depression as well as cause specific toxic effects or death. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Acetaminophen Overdosage Symptoms of Acetaminophen Overdosage Overdose of acetaminophen may cause dose-dependent potentially fatal hepatic toxicity. Early symptoms within 24 hours after the overdose may include anorexia, nausea, vomiting, diaphoresis, general malaise, and abdominal pain. The patient may then present no symptoms, but evidence of liver dysfunction may become apparent up to 72 hours after ingestion, with elevated serum transaminase and lactic dehydrogenase levels, an increase in serum bilirubin concentrations, and a prolonged prothrombin time. Death from hepatic failure may result 3 to 7 days after overdosage. Because clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion, liver function studies should be obtained initially and repeated at 24-hour intervals. Acute renal failure may accompany the hepatic dysfunction and has been noted in patients who do not exhibit signs of fulminant hepatic failure. Typically, renal impairment is more apparent 6 to 9 days after ingestion of the overdose. Treatment of Acetaminophen Overdosage In all cases of suspected overdose, immediately call the Rocky Mountain Poison Center's toll-free number (800-525-6115) for assistance in diagnosis and for directions in the use of N-acetylcysteine as an antidote. Patients' estimates of the quantity of a drug ingested are notoriously unreliable. Therefore, if an acetaminophen overdose is suspected, a serum acetaminophen assay should be obtained as early as possible, but no sooner than 4 hours following ingestion. The antidote, N-acetylcysteine, should be administered as early as possible, and within 16 hours of the overdose ingestion for optimal results. DOSAGE AND ADMINISTRATION Darvocet-N is intended for the management of mild to moderate pain. The dose should be individually adjusted according to severity of pain, patient response and patient size. Darvocet-N 100 (100 mg propoxyphene napsylate and 650 mg acetaminophen) The usual dosage is one tablet every 4 hours orally as needed for pain. The maximum dose of DARVOCET-N 100 is 6 tablets per day. Do not exceed the maximum daily dose. Darvocet-N 50 (50 mg propoxyphene napsylate and 325 mg acetaminophen) The usual dosage is two tablets every 4 hours orally as needed for pain. The maximum dose of DARVOCET-N 50 is 12 tablets per day. Do not exceed the maximum daily dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients receiving propoxyphene and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted. Consideration should be given to a reduced total daily dosage in elderly patients and in patients with hepatic or renal impairment. Cessation of Therapy For patients who used Darvocet-N on a regular basis for a period of time, when therapy with Darvocet-N is no longer needed for the treatment of their pain, it may be useful to gradually discontinue the Darvocet-N over time to prevent the development of an opioid abstinence syndrome (narcotic withdrawal). In general, therapy can be decreased by 25% to 50% per day with careful monitoring for signs and symptoms of withdrawal (see DRUG ABUSE AND DEPENDENCE for description of the signs and symptoms of withdrawal). If the patient develops these signs or symptoms, the dose should be raised to the previous level and titrated down more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. HOW SUPPLIED Darvocet-N Tablets are available in: The 50 mg tablets are dark orange, capsule shaped, film-coated and imprinted with the script "DARVOCET-N 50" on one side of the tablet, using edible black ink. They are available as follows: Bottles of 100 NDC 66479-514-10 The 100 mg tablets are dark orange, capsule shaped, film-coated, and imprinted with the script "DARVOCET-N 100" on one side of the tablet, using edible black ink. They are available as follows: Bottles of 100 NDC 66479-515-10 Bottles of 500 NDC 66479-515-50 Store at 25°C (77°F); excursions are permitted to 15°- 30°C (59°- 86°F) [see USP Controlled Room Temperature]. Inform patients of the availability of a Medication Guide for Darvocet-N that accompanies each prescription dispensed. Instruct patients to read the Darvocet-N Medication Guide prior to using Darvocet-N. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Darvon, Darvon-N, Darvocet-N and Darvocet are registered trademarks of Xanodyne Pharmaceuticals, Inc. © 2009 Xanodyne Pharmaceuticals, Inc. Company logo Newport, KY 41071 PI-514/515-A REV. 09/2009 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:09.419422	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017122s061s062lbl.pdf', 'application_number': 17122, 'submission_type': 'SUPPL ', 'submission_number': 62}
10,975	RETIN-A® Cream Gel Liquid (tretinoin) For Topical Use Only Prescribing Information Description: RETIN-A Gel, Cream, and Liquid, containing tretinoin are used for the topical treatment of acne vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or 0.01% by weight, in a gel vehicle of butyl alcohol, hydroxypropyl cellulose and alcohol (denatured with tert- butylated hydroxytoluene, and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid and has the following structure: Leave space for structure. Clinical Pharmacology: Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. Indications and Usage: RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the long-term use of this product in the treatment of other disorders have not been established. Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is noted. Warnings: GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Precautions: General: If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN- A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of RETIN-A is begun. Carcinogenesis, Mutagenesis, Impairment to Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light form a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with RETIN-A has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical does adjusted for total body surface area). Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic does adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic does adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of RETIN-A. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic effects: Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RETIN-A is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established. Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions: The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of therapy (see Dosage and Administration Section). Overdosage: If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. Dosage and Administration: RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: the liquid may be applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it, to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient. Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less frequent applications, or other dosage forms. Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be cleansed thoroughly before the medication is applied. (See Precautions) How Supplied: RETIN-A (tretinoin) is supplied as: RETIN-A Cream NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0165-01 0.025% Cream 20g 0062-0165-02 0.025% Cream 45g 0062-0175-12 0.05% Cream 20g 0062-0175-13 0.05% Cream 45g 0062-0275-23 0.1% Cream 20g 0062-0275-01 0.1% Cream 45g RETIN-A Gel NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0575-44 0.01% Gel 15g 0062-0575-46 0.01% Gel 45g 0062-0475-42 0.025% Gel 15g 0062-0475-45 0.025% Gel 45g RETIN-A Liquid NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0075-07 0.05% Liquid 28 mL Storage Conditions: RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN- A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RETIN-A® PATIENT INSTRUCTIONS Cream Gel Liquid (tretinoin) Acne Treatment For Topical Use Only IMPORTANT Read Directions Carefully Before Using THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. WARNINGS RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). PRECAUTIONS The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you do become sunburned, stop your therapy with RETIN-A until your skin has recovered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or crusted. If you are experiencing severe or persistent irritation, discontinues the use of RETIN-A and consult your physician. There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when the skin was allowed to adjust to RETIN-A or therapy was discontinued. Use other medication only on your physician’s advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and hair permanent solutions. Do not allow anyone else to use this medication. Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you have used in the past might cause unnecessary redness or peeling. If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are nursing a baby, consult your physician before using the medication. AND WHILE YOU’RE ON RETIN-A THERAPY Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be sufficient). Pat skin dry with a towel. Let the face dry 20-30 minutes before applying RETIN-A. Remember, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician, etc., may worsen your acne. HOW TO USE RETIN-A (TRETINOIN) To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN, FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF YOU HAVE QUESTIONS, ASK YOU DOCTOR. To help you use the medication correctly, keep these simple instructions in mind. (Insert picture) • Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise, especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First, wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation. • It is better not to use more than the amount suggested by your physician or to apply more frequently than instructed. Too much may irritate the skin, waste medication and won’t give faster or better results. • Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from these areas when applying. • RETIN-A Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin cream) Cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. • RETIN-A Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin gel) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected are. Smooth gently into the skin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • RETIN-A Liquid. RETIN-A (tretinoin liquid) Liquid may be applied to the skin where acne lesions appear, spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into area where treatment is not intended (such as corners of the mouth, eyes, and nose). • It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage it is important to continue using RETIN-A. If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop treatment at the first signs of improvement. Once your acne is under control you should continue regular application of RETIN-A until your physician instructs otherwise. IF YOU HAVE QUESTIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A (tretinoin), call our toll-free number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday through Friday. Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Markham Luke 6/10/02 11:40:52 AM Acting for Dr. Jonathan Wilkin, Division Director, DDDDP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:09.566774	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf', 'application_number': 17340, 'submission_type': 'SUPPL ', 'submission_number': 32}
10,974	515083-0811 August 2011 XENON Xe 133 GAS FOR DIAGNOSTIC USE DESCRIPTION: Xenon Xe 133 Gas is supplied in a mixture of xenon gas (5%) in carbon dioxide (95%). It is contained within septum sealed glass vials and is suitable for inhalation in the diagnostic evaluation of pulmonary function and imaging, as well as assessment of cerebral blood flow. Xenon Xe 133 Gas is reactor-produced as a by-product of Uranium U235 fission. Each vial contains the labeled amount of Xenon Xe 133 radioactivity at the time of calibration. The contents of the vial are in gaseous form, contain no preservatives, and are ready for use. Xenon Xe 133 is chemically and physiologically related to elemental Xenon, a non-radioactive monoatomic gas which is physiologically inert except for anesthetic properties at high doses. PHYSICAL CHARACTERISTICS Xenon Xe 133 decays by beta and gamma emissions with a half-life of 5.245 days.1 Significant radiations which are emitted by the nuclide are listed in Table 1. Table 1. Principal Radiation Emission Data from Xenon-133 Mean Mean % per Radiation Energy (KeV) Disintegration Beta-2 100.6 99.3 Ce-K-2 45.0 53.3 Ce-L-2 75.3 8.1 Ce-M-2 79.8 1.7 Gamma-2 81.0 36.5 Kα2X-ray 30.6 13.6 Kα1X-ray 31.0 25.3 KβX-ray 35.0 9.1 1Kocher, David C., "Radioactive Decay Data Tables," DOE/TIC-11026, p. 138,1981. EXTERNAL RADIATION The specific gamma ray constant for Xenon Xe 133 is 3.6 microcoulombs/Kg-MBq-hr (0.51R/hr-mCi) at 1 cm. The first half value thickness of lead is 0.0035 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from the interposition of various thicknesses of Pb is shown in Table 2. For example, the use of 0.20 cm of Pb will decrease the external radiation exposure by a factor of 1,000. Table 2. Radiation Attenuation by Lead Shielding cm of Pb Radiation Attenuation Factor 0.0035 0.5 0.037 10-1 0.12 10-2 0.20 10-3 0.29 10-4 Reference ID: 3014604 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To correct for physical decay of this radionuclide, the fractions that remain at selected time intervals after the time of calibration are shown in Table 3. Table 3. Xenon Xe 133 Physical Decay Chart (Half Life 5.245 days) Fraction Fraction Day Remaining Day Remaining 0* 1.000 8 .349 1 .877 9 .302 2 .768 10 .268 3 .674 11 .235 4 .591 12 .206 5 .518 13 .181 6 .452 14 .157 7 .398 Calibration Day CLINICAL PHARMACOLOGY: Xenon Xe 133 is a readily diffusible gas which is neither utilized nor produced by the body. It passes through cell membranes and freely exchanges between blood and tissue. It tends to concentrate more in body fat than in blood, plasma, water or protein solutions. In the concentrations used for diagnostic purposes it is physiologically inactive. Inhaled Xenon Xe 133 Gas will enter the alveolar wall and enter the pulmonary venous circulation via the capillaries. Most of the Xenon Xe 133 that enters the circulation from a single breath is returned to the lungs and exhaled after a single pass through the peripheral circulation. INDICATIONS AND USAGE: Inhalation of Xenon Xe 133 Gas has proved valuable for the evaluation of pulmonary function and for imaging the lungs. It may also be applied to assessment of cerebral flow. CONTRAINDICATIONS: None known. WARNINGS: Xenon Xe 133 Gas delivery systems, i.e., respirators or spirometers, and associated tubing assemblies must be leakproof to avoid loss of radioactivity into the environs not specifically protected by exhaust systems. Xenon Xe 133 adheres to some plastics and rubber and should not be allowed to stand in tubing or respirator containers. The unrecognized loss of radioactivity from the dose for administration may render the study non-diagnostic. The vial stopper contains dry natural rubber latex and may cause allergic reactions in providers or patients who are sensitive to latex. PRECAUTIONS: General Xenon Xe 133, as well as other radioactive drugs, must be handled with care and appropriate safety measures should be used to minimize radiation exposure to clinical personnel. Also, care should be taken to minimize radiation exposure to patients consistent with proper patient management. Exhaled Xenon Xe 133 Gas should be controlled in a manner that is in compliance with the appropriate regulations of the government agency authorized to license the use of radionuclides. Reference ID: 3014604 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides. Carcinogenesis, Mutagenesis, Impairment of Fertility No long term animal studies have been performed to evaluate carcinogenic potential or whether Xenon Xe 133 affects fertility in males or females. Pregnancy Category C Animal reproductive studies have not been conducted with Xenon Xe 133 Gas. It is also not known whether Xenon Xe 133 Gas can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Xenon Xe 133 Gas should be given to a pregnant woman only if clearly needed. Ideally, examination using radiopharmaceuticals, especially those elective in nature in a woman of childbearing capability, should be performed during the first few (approximately 10) days following the onset of menses. Nursing Mothers It is not known whether Xenon Xe 133 is excreted in human milk. Many drugs are excreted in human milk, therefore formula feedings should be substituted for breast feeding, because of the potential for adverse reactions in nursing infants. Pediatric Use Safety and effectiveness in the pediatric population has not been established. GERIATRIC USE: Clinical studies of Xenon Xe 133 Gas did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS: Adverse reactions related to the use of this agent have not been reported to date. DOSAGE AND ADMINISTRATION: Xenon Xe 133 Gas is administered by inhalation from closed respirator systems or spirometers. The suggested activity range employed for inhalation by the average adult patient (70 kg) is: Pulmonary function including imaging: 74-1110 MBq (2-30 mCi) in 3 liters of air. Cerebral blood flow: 370-1110 MBq (10-30 mCi) in 3 liters of air. The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. Reference ID: 3014604 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RADIATION DOSIMETRY The estimated absorbed radiation doses2 to an average patient (70 kg) for pulmonary perfusion and cerebral blood flow studies from a maximum dose of 1110 MBq (30 mCi) of Xenon Xe 133 in 3 liters of air are shown in Table 4. Table 4. Radiation Doses Effective Whole Half-Time Lungs Brain Body mGy/1110 MBq (rads/30 mCi) Pulmonary Perfusion 2 min. 2.5(0.25) 0.014(0.0014) 0.027(0.0027) Cerebral Blood Flow 5 min. 6.3(0.63) 0.035(0.0035) 0.068(0.0068) *99% of activity is in lungs. 2Method of Calculation: A Schema for Absorbed-Dose Calculation for Biologically Distributed Radionuclides, Supplement No. 1, MIRD pamphlet No. 1, J. Nucl. Med., p.7 (1968). HOW SUPPLIED: The Xenon Xe 133 Gas is supplied as part of the Calidose™ system, consisting of 3 mL unit dose vials and the Calidose™ dispenser for shielded dispensing. Normally vials containing either 370 or 740 MBq (10 or 20 mCi)/vial, packed 1 vial or 5 vials per shield tube, are supplied. The NDC number for: 10 mCi vial is 11994-127; 20 mCi vial is 11994-128. Store at controlled room temperature 20°-25°C (68°-77°F) [See USP]. This radiopharmaceutical is approved for distribution to persons licensed pursuant to the Code of Massachusetts Regulations 105 CMR 120.100 for the uses listed in 105 CMR 120.547 or 120.552 or under equivalent regulations of the U.S. Nuclear Regulatory Commission, an Agreement State, or a Licensing State. The contents of the vial are radioactive. Adequate shielding and handling precautions must be maintained. Lantheus Medical Imaging 331 Treble Cove Rd., N. Billerica, MA 01862 USA For Ordering Tel. Toll Free 800-299-3431 (For Massachusetts & International, Call 978-667-9531) All Other Business 800-362-2668 Printed in U.S.A. Reference ID: 3014604 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:09.627681	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017284s012lbl.pdf', 'application_number': 17284, 'submission_type': 'SUPPL ', 'submission_number': 12}
10,977	Rx only BACTRIM™ sulfamethoxazole and trimethoprim DS (double strength) tablets and tablets USP To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bactrim (sulfamethoxazole and trimethoprim) tablets and other antibacterial drugs, Bactrim (sulfamethoxazole and trimethoprim) tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION BACTRIM (sulfamethoxazole and trimethoprim) is a synthetic antibacterial combination product available in DS (double strength) tablets, each containing 800 mg sulfamethoxazole and 160 mg trimethoprim; in tablets, each containing 400 mg sulfamethoxazole and 80 mg trimethoprim for oral administration. Sulfamethoxazole is N1-(5-methyl-3-isoxazolyl)sulfanilamide; the molecular formula is C10H11N3O3S. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula: structural formula Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; the molecular formula is C14H18N4O3. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3 and the following structural formula: structural formula Inactive ingredients: Docusate sodium 85%, sodium benzoate 15%, sodium starch glycolate, magnesium stearate and pregelatinized starch. CLINICAL PHARMACOLOGY BACTRIM is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. Sulfamethoxazole is metabolized in humans to at least 5 metabolites: the N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl- Rev 13, June 2013 Reference ID: 3339935 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5-methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formulation of N4-hydroxy metabolite is mediated via CYP2C9. Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five are glutathione adducts and six are oxidative metabolites, including the major metabolites, 1- and 3-oxides and the 3- and 4-hydroxy derivatives. The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not a substrate of P-glycoprotein. Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole. Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION section). Detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. During administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 µg/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 µg/mL and 68.0 µg/mL, respectively. These steady-state levels were achieved after three days of drug administration.1 Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N4-acetylated metabolite.2 When administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middle ear fluid; trimethoprim also distributes to bronchial secretion, and both pass the placental barrier and are excreted in human milk. Geriatric Pharmacokinetics: The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-US approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, Rev 13, June 2013 Reference ID: 3339935 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects.3 Microbiology Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria. In vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone. Sulfamethoxazole and trimethoprim have been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobic gram-positive microorganisms: Streptococcus pneumoniae Aerobic gram-negative microorganisms: Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler’s diarrhea) Klebsiella species Enterobacter species Haemophilus influenzae Morganella morganii Proteus mirabilis Proteus vulgaris Shigella flexneri Shigella sonnei Other Organisms: Pneumocystis jiroveci Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar)4,15. The MIC values should be interpreted according to the criteria provided in Table 1. Rev 13, June 2013 Reference ID: 3339935 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method14,15. This procedure uses paper disks impregnated with 1.25/23.75 µg of trimethoprim/sulfamethoxazole to test the susceptibility of microorganisms to trimethoprim/sulfamethoxazole. The disc diffusion interpretive criteria are provided in Table 1. Table 1: Susceptibility Test Interpretive Criteria for Trimethoprim/Sulfamethoxazole Bacteria Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) S I R S I R Enterobacteriaceae ≤ 2/38 - ≥ 4/76 ≥ 16 11 – 15 ≤ 10 Haemophilus influenzae ≤ 0.5/9.5 1/19 – 2/38 ≥ 4/76 ≥ 16 11 – 15 ≤ 10 Streptococcus pneumoniae ≤ 0.5/9.5 1/19 – 2/38 ≥ 4/76 ≥ 19 16 – 18 ≤ 15 A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay and the techniques of the individuals performing the test4, 14, 15. Standard trimethoprim/sulfamethoxazole powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 1.25/23.75 µg trimethoprim/sulfamethoxazole disk the criteria in Table 2 should be achieved. Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Trimethoprim/Sulfamethoxazole QC Strain Minimal Inhibitory Zone Diameter Concentration (mm) (mcg/mL) Escherichia coli ATCC 25922 ≤ 0.5/9.5 23–29 Haemophilus influenzae ATCC 49247 0.03/0.59 – 0.25/4.75 24–32 Streptococcus pneumoniae ATCC 49619 0.12/2.4 – 1/19 20–28 Rev 13, June 2013 Reference ID: 3339935 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bactrim (sulfamethoxazole and trimethoprim) tablets and other antibacterial drugs, Bactrim (sulfamethoxazole and trimethoprim) tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to empiric selection of therapy. Urinary Tract Infections: For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination. Acute Otitis Media: For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of other antimicrobial agents. To date, there are limited data on the safety of repeated use of BACTRIM in pediatric patients under two years of age. BACTRIM is not indicated for prophylactic or prolonged administration in otitis media at any age. Acute Exacerbations of Chronic Bronchitis in Adults: For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when a physician deems that BACTRIM could offer some advantage over the use of a single antimicrobial agent. Shigellosis: For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated. Pneumocystis jiroveci Pneumonia: For the treatment of documented Pneumocystis jiroveci pneumonia and for prophylaxis against P. jiroveci pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing P. jiroveci pneumonia. Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea due to susceptible strains of enterotoxigenic E. coli. CONTRAINDICATIONS BACTRIM is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides, in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides, and in patients with documented megaloblastic anemia due to folate deficiency. BACTRIM is contraindicated in pediatric patients less than 2 months of age. BACTRIM is also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored. Rev 13, June 2013 Reference ID: 3339935 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Embryofetal Toxicity Some epidemiologic studies suggest that exposure to sulfamethoxazole/trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If sulfamethoxazole/trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus. Hypersensitivity and Other Fatal Reactions Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. Sulfonamides, including sulfonamide-containing products such as sulfamethoxazole/trimethoprim, should be discontinued at the first appearance of skin rash or any sign of adverse reaction. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders (see PRECAUTIONS). Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions. Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment. Thrombocytopenia Sulfamethoxazole/trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole/trimethoprim. Streptococcal Infections and Rheumatic Fever The sulfonamides should not be used for treatment of group A -hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever. Clostridium difficile associated diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BACTRIM, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Rev 13, June 2013 Reference ID: 3339935 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Adjunctive treatment with Leucovorin for Pneumocystis jiroveci pneumonia Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jiroveci pneumonia in a randomized placebo controlled trial.6 Co-administration of trimethoprim sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided. PRECAUTIONS Development of drug resistant bacteria Prescribing Bactrim (sulfamethoxazole and trimethoprim) tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Folate deficiency BACTRIM should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states) and to those with severe allergies or bronchial asthma. Hematological changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy. Hemolysis In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Hypoglycemia Cases of hypoglycemia in non-diabetic patients treated with BACTRIM are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of BACTRIM are particularly at risk. Phenylalanine metabolism Trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction. Porphyria and Hypothyroidism As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction. Use in the Treatment of and Prophylaxis for Pneumocystis jiroveci Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS): AIDS patients may not tolerate or respond to Rev 13, June 2013 Reference ID: 3339935 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BACTRIM in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with BACTRIM therapy in AIDS patients who are being treated for P. jiroveci pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of BACTRIM in non-AIDS patients. Adverse effects are generally less severe in patients receiving BACTRIM for prophylaxis. A history of mild intolerance to BACTRIM in AIDS patients does not appear to predict intolerance of subsequent secondary prophylaxis.7 However, if a patient develops skin rash or any sign of adverse reaction, therapy with BACTRIM should be reevaluated (see WARNINGS). Co-administration of BACTRIM and leucovorin should be avoided with P. jiroveci pneumonia (see WARNINGS). Electrolyte Abnormalities High dosage of trimethoprim, as used in patients with P. jiroveci pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients. Severe and symptomatic hyponatremia can occur in patients receiving BACTRIM, particularly for the treatment of P. jiroveci pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications. During treatment, adequate fluid intake and urinary output should be ensured to prevent crystalluria. Patients who are “slow acetylators” may be more prone to idiosyncratic reactions to sulfonamides. Information for Patients: Patients should be counseled that antibacterial drugs including Bactrim (sulfamethoxazole and trimethoprim) tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Bactrim (sulfamethoxazole and trimethoprim) tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Bactrim (sulfamethoxazole and trimethoprim) tablets or other antibacterial drugs in the future. Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Rev 13, June 2013 Reference ID: 3339935 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests: Complete blood counts should be done frequently in patients receiving BACTRIM; if a significant reduction in the count of any formed blood element is noted, BACTRIM should be discontinued. Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function. Drug Interactions: Potential for BACTRIM to Affect Other Drugs Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Caution is recommended when Bactrim is co-administered with drugs that are substrates of CYP2C8 and 2C9 or OCT2. In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. It has been reported that BACTRIM may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when BACTRIM is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. BACTRIM may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). BACTRIM, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. There have been reports of marked but reversible nephrotoxicity with coadministration of BACTRIM and cyclosporine in renal transplant recipients. Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. Serum digoxin levels should be monitored. Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin. Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if BACTRIM is prescribed. The efficacy of tricyclic antidepressants can decrease when coadministered with BACTRIM. BACTRIM potentiates the effect of oral hypoglycemics that are metabolized by CYP2C8 (e.g., pioglitazone, repaglinide, and rosiglitazone) or CYP2C9 (e.g., glipizide and glyburide) or eliminated renally via OCT2 (e.g., metformin). Additional monitoring of blood glucose may be warranted. Rev 13, June 2013 Reference ID: 3339935 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole/trimethoprim and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine and metformin, have also been reported. In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole/trimethoprim and an angiotensin converting enzyme inhibitor.8,9 Drug/Laboratory Test Interactions: BACTRIM, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA). The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2.4-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole b.i.d.). Mutagenesis: In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities. Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro micronucleus assays using cultured human lymphocytes. Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes, trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded. Impairment of Fertility: No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim, doses roughly two times the recommended human daily dose on a body surface area basis. Pregnancy: While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or sulfamethoxazole and Rev 13, June 2013 Reference ID: 3339935 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda trimethoprim. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving sulfamethoxazole and trimethoprim. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, BACTRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratogenic Effects: Pregnancy Category D. Human Data: While there are no large prospective, well controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole/trimethoprim with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons. Alternatively, other epidemiologic studies did not detect statistically significant associations between sulfamethoxazole/trimethoprim exposure and specific malformations. Animal Data: In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area. Nonteratogenic Effects: See CONTRAINDICATIONS section. Nursing Mothers: Levels of trimethoprim/sulfamethoxazole in breast milk are approximately 2– 5% of the recommended daily dose for infants over 2 months of age. Caution should be exercised when BACTRIM is administered to a nursing woman, especially when breastfeeding, jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and kernicterus. Pediatric Use: BACTRIM is contraindicated for infants younger than 2 months of age (see INDICATIONS and CONTRAINDICATIONS sections). Geriatric Use: Clinical studies of BACTRIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Rev 13, June 2013 Reference ID: 3339935 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions (see DOSAGE AND ADMINISTRATION section). The trimethoprim component of BACTRIM may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of BACTRIM treatment is recommended to help lower potassium serum levels. Bactrim Tablets contain 1.8 mg sodium (0.08 mEq) of sodium per tablet. Bactrim DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet. Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics). ADVERSE REACTIONS The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS (SEE WARNINGS SECTION). Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia. Allergic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch- Schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported. Gastrointestinal: Hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia. Rev 13, June 2013 Reference ID: 3339935 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Genitourinary: Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine. Metabolic and Nutritional: Hyperkalemia, hyponatremia (see PRECAUTIONS: Electrolyte Abnormalities). Neurologic: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache. Psychiatric: Hallucinations, depression, apathy, nervousness. Endocrine: The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Musculoskeletal: Arthralgia and myalgia. Isolated cases of rhabdomyolysis have been reported with BACTRIM, mainly in AIDS patients. Respiratory: Cough, shortness of breath and pulmonary infiltrates (see WARNINGS). Miscellaneous: Weakness, fatigue, insomnia. Postmarketing Experience The following adverse reactions have been identified during post-approval use of trimethoprim sulfamethoxazole. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure:  Thrombotic thrombocytopenia purpura  Idiopathic thrombocytopenic purpura  QT prolongation resulting in ventricular tachycardia and torsade de pointes OVERDOSAGE Acute: The amount of a single dose of BACTRIM that is either associated with symptoms of overdosage or is likely to be life-threatening has not been reported. Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria may be noted. Blood dyscrasias and jaundice are potential late manifestations of overdosage. Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression. General principles of treatment include the institution of gastric lavage or emesis, forcing oral fluids, and the administration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient Rev 13, June 2013 Reference ID: 3339935 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating sulfamethoxazole and trimethoprim. Chronic: Use of BACTRIM at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin 5 to 15 mg daily until normal hematopoiesis is restored. DOSAGE AND ADMINISTRATION BACTRIM is contraindicated in pediatric patients less than 2 months of age. Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children: Adults: The usual adult dosage in the treatment of urinary tract infections is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. Children: The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given in two divided doses every 12 hours for 10 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. The following table is a guideline for the attainment of this dosage: Children 2 months of age or older: Weight Dose–every 12 hours lb kg Tablets 22 10 – 44 20 1 66 30 1½ 88 40 2 or 1 DS tablet For Patients with Impaired Renal Function: When renal function is impaired, a reduced dosage should be employed using the following table: Creatinine Recommended Clearance (mL/min) Dosage Regimen Above 30 Usual standard regimen 15–30 ½ the usual regimen Below 15 Use not recommended Acute Exacerbations of Chronic Bronchitis in Adults: The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 14 days. Rev 13, June 2013 Reference ID: 3339935 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pneumocystis Jiroveci Pneumonia: Treatment: Adults and Children: The recommended dosage for treatment of patients with documented Pneumocystis jiroveci pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days.11 The following table is a guideline for the upper limit of this dosage: Weight Dose–every 6 hours lb kg Tablets 18 8 – 35 16 1 53 24 1½ 70 32 2 or 1 DS tablet 88 40 2½ 106 48 3 or 1½ DS tablets 141 64 4 or 2 DS tablets 176 80 5 or 2½ DS tablets For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table. Prophylaxis: Adults: The recommended dosage for prophylaxis in adults is 1 BACTRIM DS (double strength) tablet daily.12 Children: For children, the recommended dose is 750 mg/m2/day sulfamethoxazole with 150 mg/m2/day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim.13 The following table is a guideline for the attainment of this dosage in children: Body Surface Area Dose–every 12 hours (m2) Tablets 0.26 – 0.53 ½ 1.06 1 Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea, the usual adult dosage is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 5 days. Rev 13, June 2013 Reference ID: 3339935 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED BACTRIM™ TABLETS are supplied as follows: BACTRIM™ DS (double strength) TABLETS (white, oval shaped, scored) containing 160 mg trimethoprim and 800 mg sulfamethoxazole – bottles of 100 (NDC 13310-146-01) and 500 (NDC 13310-146-05). Imprint on tablets (debossed): (front) BACTRIM DS BACTRIM™ TABLETS (white, round, scored) containing 80 mg trimethoprim and 400 mg sulfamethoxazole – bottles of 100 (NDC 13310-145-01) and 500 (NDC 13310-145-05). Imprint on tablets (debossed): (front) BACTRIM Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature] DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER. REFERENCES: 1. Kremers P, Duvivier J, Heusghem C. Pharmacokinetic Studies of Co-Trimoxazole in Man after Single and Repeated Doses. J Clin Pharmacol. Feb-Mar 1974; 14:112–117. 2. Kaplan SA, et al. Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man. J Infect Dis. Nov 1973; 128 (Suppl): S547–S555. 3. Varoquaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol. 1985;20:575–581. 4. Rudoy RC, Nelson JD, Haltalin KC. Antimicrobial Agents Chemother. May 1974;5:439–443. 5. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 9th ed. CLSI document M07– A9, CLSI, Wayne, PA, 2012. 6. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994 Oct;170(4):912–7. 7. Hardy DW, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1992; 327: 1842–1848. 8. Marinella Mark A. 1999. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontol. 45:209–212. 9. Margassery, S. and B. Bastani. 2002. Life threatening hyperkalemia and acidosis secondary to trimethoprim-sulfamethoxazole treatment. J. Nephrol. 14:410–414. 10. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973; 128 (Suppl):S657–S663. 11. Masur H. Prevention and treatment of Pneumocystis pneumonia. N Engl J Med. 1992; 327: 1853–1880. 12. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR. 1992; 41(RR–4):1–11. 13. CDC Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR. 1991; 40(RR–2):1–13. 14. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 11th ed. CLSI document M02–A11, CLSI, Wayne, PA, 2012. Rev 13, June 2013 Reference ID: 3339935 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100–S23. CLSI document M100–S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013. BACTRIMTM and BACTRIMTM DS are trademarks of Hoffmann-La Roche Inc. Manufactured for: AR SCIENTIFIC, INC. Philadelphia, PA 19124 USA by: MUTUAL PHARMACEUTICAL COMPANY, INC. Philadelphia, PA 19124 USA Rev 13, June 2013 Rev 13, June 2013 Reference ID: 3339935 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:09.698730	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017377s068s073lbl.pdf', 'application_number': 17377, 'submission_type': 'SUPPL ', 'submission_number': 68}
10,976	only BACTRIM™ brand of sulfamethoxazole and trimethoprim DS (double strength) TABLETS and TABLETS, USP DESCRIPTION BACTRIM (sulfamethoxazole and trimethoprim) is a syn- thetic antibacterial combination product available in DS (double strength) tablets, each containing 800 mg sul- famethoxazole and 160 mg trimethoprim; in tablets, each containing 400 mg sulfamethoxazole and 80 mg trimetho- prim for oral administration. Sulfamethoxazole is N1 - (5-methyl-3-isoxazolyl) sulfanil- amide; the molecular formula is C10H11N3O3S. It is almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula: Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; the molecular formula is C14H18N4O3. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3. It has the following struc- tural formula: Inactive ingredients: Docusate sodium 85%, sodium benzoate 15%, sodium starch glycolate, magnesium stearate and pregelatinized starch. CLINICAL PHARMACOLOGY BACTRIM is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N4-acetylation, although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole. Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION section). Detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. During administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady- state plasma concentration of trimethoprim was 1.72 µg/mL. The steady-state mean plasma levels of free and total sul- famethoxazole were 57.4 µg/mL and 68.0 µg/mL, respectively. These steady-state levels were achieved after three days of drug administration.1 Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular fil- tration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty per- cent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N4-acetylated metabolite.2 When administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middle ear fluid; trimethoprim also distributes to bronchial secretion, and both pass the placental barrier and are excreted in human milk. Geriatric Pharmacokinetics: The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-US approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects.3 Microbiology Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria. In vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone. Sulfamethoxazole and trimethoprim have been shown to be active against most strains of the following microor- ganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobic gram-positive microorganisms: Streptococcus pneumoniae Aerobic gram-negative microorganisms: Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler’s diarrhea) Klebsiella species Enterobacter species Haemophilus influenzae Morganella morganii Proteus mirabilis Proteus vulgaris Shigella flexneri3 Shigella sonnei3 Other Organisms: Pneumocystis carinii Susceptibility Testing Methods: Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be deter- mined using a standardized procedure. Standardized procedures are based on a dilution method4 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of sul- famethoxazole/trimethoprim powder. The MIC values should be interpreted according to the following criteria: For testing Enterobacteriaceae: MIC (µg/mL) Interpretation ≤2/38 Susceptible (S) ≥4/76 Resistant (R) When testing either Haemophilus influenzaea or Streptococcus pneumoniaeb: MIC (µg/mL) Interpretationb ≤0.5/9.5 Susceptible (S) 1/19-2/38 Intermediate (I) ≥4/76 Resistant (R) a. These interpretative standards are applicable only to broth microdilution susceptibility tests with Haemophilus influenzae using Haemophilus Test Medium (HTM)4. b. These interpretative standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood4. A report of "Susceptible" indicated that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not frilly susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also pro- vides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in inter- pretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard sulfamethoxazole/trimethoprim powder should pro- vide the following range of values: Microorganism MIC (µg/mL) Escherichia coli ATCC 25922 ≤0.5/9.5 Haemophilus influenzaec ATCC 49247 0.03/0.59 - 0.25/4.75 Streptococcus pneumoniaed ATCC 49619 0.12/2.4 — 1/19 c. This quality control range is applicable only to Haemophilus influenzae ATCC 49247 tested by broth microdilution procedure using Haemophilus Test Medium (HTM)4. d. This quality control range is applicable to tests performed by the broth microdilution method only using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood4. Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the sus- ceptibility of bacteria to antimicrobial compounds. One such standardized procedure5 requires the use of stan- dardized inoculum concentrations. This procedure uses paper disks impregnated with 1.25/23.75 µg of sulfamethoxazole/trimethoprim to test the susceptibility of microorganisms to sulfamethoxazole/trimethoprim. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 1.25/23.75 µg of sulfamethoxazole/trimethoprim disk should be interpreted according to the following criteria: For testing either Enterobacteriaceae or Haemophilus influenzaee : Zone Diameter (mm) Interpretation ≥16 Susceptible (S) 11 - 15 Intermediate (I) ≤10 Resistant (R) e. These zone diameter standards are applicable only for disk diffusion testing with Haemophilus influenzae and Haemophilus Test Medium (HTM)5. When testing Streptococcus pneumoniaef: Zone Diameter (mm) Interpretation ≥19 Susceptible (S) 16 – 18 Intermediate (I) ≤15 Resistant (R) f. These zone diameter interpretative standards are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood when incubated in 5% CO25. Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for sulfamethoxazole/trimethoprim. Quality Control As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 1.25/23.75 µg sulfamethoxazole/trimethoprim disk* should provide the following zone diameters in these labora- tory test quality control strains: Microorganism Zone Diameter Ranges (mm) Escherichia coli ATCC 25922 24-32 Haemophilus influenzaeg ATCC 49247 24-32 Streptococcus pneumoniaeh ATCC 49619 20-28 *Mueller-Hinton agar should be checked for excessive levels of thymidine or thymine. To determine whether Mueller-Hinton medium has sufficiently low levels of thymidine and thymine, an Enterococcus faecalis (ATCC 29212 or ATCC 33186) may be tested with sulfamethoxazole/trimethoprim disks. A zone of inhibition ≥20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine. g. This quality control range is applicable only to Haemophilus influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM)5. h. This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood when incubated in 5% CO25 . INDICATIONS AND USAGE Urinary Tract Infections: For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination. Acute Otitis Media: For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician sulfamethoxa- zole and trimethoprim offers some advantage over the use of other antimicrobial agents. To date, there are limited data on the safety of repeated use of BACTRIM in pediatric patients under two years of age. BACTRIM is not indicated for prophylactic or prolonged administration in otitis media at any age. Acute Exacerbations of Chronic Bronchitis in Adults: For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician BACTRIM offers some advantage over the use of a single antimicrobial agent. Shigellosis: For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated. Pneumocystis Carinii Pneumonia: For the treatment of documented Pneumocystis carinii pneumonia and for prophylaxis against Pneumocystis carinii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis carinii pneumonia. Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea due to susceptible strains of enterotoxi- genic E. coli. CONTRAINDICATIONS BACTRIM is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides and in patients with documented megaloblastic anemia due to folate deficiency. BACTRIM is also contraindicated in preg- nant patients and nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. BACTRIM is contraindicated in pediatric patients less than 2 months of age. BACTRIM is also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored. WARNINGS FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPI- DERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS. SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH AS SULFAMETHOXA- ZOLE/TRIMETHOPRIM, SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders (see PRECAUTIONS). Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions. Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment. The sulfonamides should not be used for treatment of group A -hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including sul- famethoxazole/trimethoprim, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the adminis- tration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis." After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an anti-bacterial drug effective against C. difficile. PRECAUTIONS General: BACTRIM should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states) and to those with severe allergies or bronchial asthma. In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is fre- quently dose-related. (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Cases of hypoglycemia in non-diabetic patients treated with BACTRIM are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of BACTRIM are particularly at risk. Hematological changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy. Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylke- tonuric patients on appropriate dietary restriction. As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction. Use in the Treatment of and Prophylaxis for Pneumocystis Carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS): AIDS patients may not tolerate or respond to BACTRIM in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with BACTRIM therapy in AIDS patients who are being treated for Pneumocystis carinii pneumonia has been reported to be greatly increased compared with the incidence nor- mally associated with the use of BACTRIM in non-AIDS patients. The incidence of hyperkalemia appears to be increased in AIDS patients receiving BACTRIM. Adverse effects are generally less severe in patients receiving BACTRIM for prophylaxis. A history of mild intolerance to BACTRIM in AIDS patients does not appear to pre- dict intolerance of subsequent secondary prophylaxis.6 However, if a patient develops skin rash or any sign of adverse reaction, therapy with BACTRIM should be reevaluated (see WARNINGS). High dosage of trimethoprim, as used in patients with Pneumocystis carinii pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treat- ment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyper- kalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients. During treatment, adequate fluid intake and urinary output should be ensured to prevent crystalluria. Patients who &64248-AAEJJd 6 4 2 4 8 - 0 0 4 - 9 9 N 3 3 312 H2N SO2NH N O CH3 N N NH2 NH2 CH2 OCH3 OCH3 CH3O This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda are "slow acetylators" may be more prone to idiosyncratic reactions to sulfonamides. Information for Patients: Patients should be instructed to maintain an adequate fluid intake in order to pre- vent crystalluria and stone formation. Laboratory Tests: Complete blood counts should be done frequently in patients receiving BACTRIM; if a sig- nificant reduction in the count of any formed blood element is noted, BACTRIM should be discontinued. Uri- nalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function. Drug Interactions: In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. It has been reported that BACTRIM may prolong the prothrombin time in patients who are receiving the anti- coagulant warfarin. This interaction should be kept in mind when BACTRIM is given to patients already on anti- coagulant therapy, and the coagulation time should be reassessed. BACTRIM may inhibit the hepatic metabolism of phenytoin. BACTRIM, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. There have been reports of marked but reversible nephrotoxicity with coadministration of BACTRIM and cyclosporine in renal transplant recipients. Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. Serum digoxin levels should be monitored. Increased sulfamethoxazole blood levels may occur in patients who are receiving indomethacin. Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if BACTRIM is prescribed. The efficacy of tricyclic antidepressants can decrease when coadministered with BACTRIM. Like other sulfonamide-containing drugs, BACTRIM potentiates the effect of oral hypoglycemics. In the literature, a single case of toxic delirium has been reported after concomitant intake of trimethoprim/sul- famethoxazole and amantadine. Drug/Laboratory Test Interactions: BACTRIM, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihy- drofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA). The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Long-term studies in animals to evaluate carcinogenic potential have not been conducted with BACTRIM. Mutagenesis: Bacterial mutagenic studies have not been performed with sulfamethoxazole and trimethoprim in combination. Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. No chromosomal damage was observed in human leukocytes in vitro with sulfamethoxazole and trimethoprim alone or in combination; the concentrations used exceeded blood levels of these compounds following therapy with sulfamethoxazole and trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities. Impairment of Fertility: No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim. Pregnancy: Teratogenic Effects: Pregnancy Category C. In rats, oral doses of 533 mg/kg or 200 mg/kg pro- duced teratologic effects manifested mainly as cleft palates. The highest dose which did not cause cleft palates in rats was 512 mg/kg or 192 mg/kg trimethoprim when admin- istered separately. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In one study, however, cleft palates were observed in one litter out of 9 when 355 mg/kg of sulfamethoxazole was used in combination with 88 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed and malformed conceptuses) was asso- ciated with doses of trimethoprim 6 times the human therapeutic dose. While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,7 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or sulfamethoxazole and trimethoprim. The incidence of congenital abnor- malities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving sulfamethox- azole and trimethoprim. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 chil- dren whose mothers had received oral sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, BACTRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: See CONTRAINDICATIONS section. Nursing Mothers: See CONTRAINDICATIONS section. Pediatric Use: BACTRIM is not recommended for infants younger than 2 months of age (see INDICATIONS and CONTRAINDICATIONS sections). Geriatric Use: Clinical studies of BACTRIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), or a specific decrease in platelets (with or without purpura) are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions (see DOSAGE AND ADMINISTRATION section). The trimethoprim component of BACTRIM may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia. Close monitoring of serum potassium is warranted in these patients. Discontinuation of BACTRIM treatment is recommended to help lower potassium serum levels. Bactrim Tablets contain 1.8 mg sodium (0.08 mEq) of sodium per tablet. Bactrim DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet. Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult sub- jects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimetho- prim was lower in geriatric subjects compared with younger subjects (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics). ADVERSE REACTIONS The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SUL- FONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS- JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS (SEE WARNINGS SECTION). Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia. Allergic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunc- tival and scleral injection, pruritus, urticaria and rash. In addition, periarteritis nodosa and systemic lupus ery- thematosus have been reported. Gastrointestinal: Hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transami- nase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdom- inal pain, diarrhea, anorexia. Genitourinary: Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with olig- uria and anuria, crystalluria and nephrotoxicity in association with cyclosporine. Metabolic and Nutritional: Hyperkalemia (see PRECAUTIONS: Use in the Treatment of and Prophylaxis for Pneumocystis Carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS). Neurologic: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache. Psychiatric: Hallucinations, depression, apathy, nervousness. Endocrine: The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Musculoskeletal: Arthralgia and myalgia. Isolated cases of rhabdomyolysis have been reported with BACTRIM, mainly in AIDS patients. Respiratory: Cough, shortness of breath and pulmonary infiltrates (see WARNINGS). Miscellaneous: Weakness, fatigue, insomnia. OVERDOSAGE Acute: The amount of a single dose of BACTRIM that is either associated with symptoms of overdosage or is likely to be life-threatening has not been reported. Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hema- turia and crystalluria may be noted. Blood dyscrasias and jaundice are potential late manifestations of overdosage. Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression. General principles of treatment include the institution of gastric lavage or emesis, forcing oral fluids, and the admin- istration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient should be monitored with blood counts and appro- priate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating sulfamethoxazole and trimethoprim. Chronic: Use of BACTRIM at high doses and/or for extended periods of time may cause bone marrow depres- sion manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depres- sion occur, the patient should be given leucovorin 5 to 15 mg daily until normal hematopoiesis is restored. DOSAGE AND ADMINISTRATION Not recommended for use in pediatric patients less than 2 months of age. Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children: Adults: The usual adult dosage in the treatment of urinary tract infections is 1 BACTRIM DS (double strength) tablet, 2 BACTRIM tablets every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. Children: The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given in two divided doses every 12 hours for 10 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. The following table is a guide- line for the attainment of this dosage: Children 2 months of age or older: Weight Dose--every 12 hours lb kg Tablets 22 10 - 44 20 1 66 30 1 1/2 88 40 2 or 1 DS tablet For Patients with Impaired Renal Function: When renal function is impaired, a reduced dosage should be employed using the following table: Creatinine Recommended Clearance (mL/min) Dosage Regimen Above 30 Usual standard regimen 15-30 1/2 the usual regimen Below 15 Use not recommended Acute Exacerbations of Chronic Bronchitis in Adults: The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 BACTRIM DS (double strength) tablet, 2 BACTRIM tablets every 12 hours for 14 days. Pneumocystis Carinii Pneumonia: Treatment: Adults and Children: The recommended dosage for patients with documented Pneumocystis carinii pneumonia is 75 to 100 mg/kg sul- famethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days.8 The following table is a guideline for the upper limit of this dosage. Weight Dose--every 6 hours lb kg Tablets 18 8 - 35 16 1 53 24 1 1/2 70 32 2 or 1 DS tablet 88 40 2 1/2 106 48 3 or 1 1/2 DS tablets 141 64 4 or 2 DS tablets 176 80 5 or 2 1/2 DS tablets For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table. Prophylaxis: Adults: The recommended dosage for prophylaxis in adults is 1 BACTRIM DS (double strength) tablet daily.9 Children: For children, the recommended dose is 750 mg/m2 /day sulfamethoxazole with 150 mg/m2/day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim.9 The following table is a guideline for the attainment of this dosage in children: Body Surface Area Dose--every 12 hours (m2) Tablets 0.26 - 0.53 1/2 1.06 1 Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea, the usual adult dosage is 1 BACTRIM DS (double strength) tablet; 2 BACTRIM tablets every 12 hours for 5 days. HOW SUPPLIED BACTRIM™ TABLETS are supplied as follows: BACTRIM™ DS (double strength) TABLETS (white, oval shaped, scored) containing 160 mg trimethoprim and 800 mg sulfamethoxazole – bottles of 100 (NDC 64248-117-10) and 500 (NDC 64248-117-50). Imprint on tablets (debossed): (front) BACTRIM DS; (back) WFHC. BACTRIM™ TABLETS (white, round, scored) containing 80 mg trimethoprim and 400 mg sulfamethoxazole – bottles of 100 (NDC 64248-004-10). Imprint on tablets (debossed): (front) BACTRIM; (back) WFHC. Store at controlled room temperature 15°-30°C (59°-86°F). DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER. REFERENCES: 1. Kremers P, Duvivier J, Heusghem C. Pharmacokinetic Studies of Co-Trimoxazole in Man after Single and Repeated Doses. J Clin Pharmacol. Feb-Mar 1974; 14:112-117. 2. Kaplan SA, et al. Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man. J Infect Dis. Nov 1973; 128 (Suppl): S547-S555. 3. Varoquaux O, et al Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly Br J Clin Pharmacol 1985;20;575-581 4. Rudoy RC, Nelson JD, Haltalin KC. Antimicrobial Agents Chemother. May 1974;5:439-443. 5. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Fourth Edition. NCCLS document M7-A4, Vol.17 No. 2 NCCLS, Wayne, PA, January, 1997. 6. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Sus- ceptibility Tests. Approved Standard – Sixth Edition. NCCLS Document M2-A6, Vol.17, No.1, NCCLS, Wayne, PA, January, 1997. 7. Hardy DW, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for sec- ondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syn- drome. N Engl J Med. 1992; 327:1842-1848. 8. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973; 128 (Suppl):S657-S663. 9. Masur H. Prevention and treatment of Pneumocystis pneumonia. N Engl J Med. 1992; 327:1853-1880. 10. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR. 1992; 41(RR-4):1-11. 11. CDC Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR. 1991; 40(RR-2):1-13. Manufactured for: WOMEN FIRST HEALTHCARE, INC. San Diego, CA 92130 www.womenfirst.com by: MUTUAL PHARMACEUTICAL COMPANY, INC. Philadelphia, PA 19124 BA-02-04-1 Revised: July 2002Ch This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Janice Soreth 10/17/02 04:30:19 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:09.815552	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17377s58lbl.pdf', 'application_number': 17377, 'submission_type': 'SUPPL ', 'submission_number': 58}
10,978	Rx only BACTRIM™ sulfamethoxazole and trimethoprim DS (double strength) tablets and tablets USP To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bactrim (sulfamethoxazole and trimethoprim) tablets and other antibacterial drugs, Bactrim (sulfamethoxazole and trimethoprim) tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION BACTRIM (sulfamethoxazole and trimethoprim) is a synthetic antibacterial combination product available in DS (double strength) tablets, each containing 800 mg sulfamethoxazole and 160 mg trimethoprim; in tablets, each containing 400 mg sulfamethoxazole and 80 mg trimethoprim for oral administration. Sulfamethoxazole is N1-(5-methyl-3-isoxazolyl)sulfanilamide; the molecular formula is C10H11N3O3S. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula: structural formula Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; the molecular formula is C14H18N4O3. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3 and the following structural formula: structural formula Inactive ingredients: Docusate sodium 85%, sodium benzoate 15%, sodium starch glycolate, magnesium stearate and pregelatinized starch. CLINICAL PHARMACOLOGY BACTRIM is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. Sulfamethoxazole is metabolized in humans to at least 5 metabolites: the N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl- Rev 13, June 2013 Reference ID: 3339935 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5-methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formulation of N4-hydroxy metabolite is mediated via CYP2C9. Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five are glutathione adducts and six are oxidative metabolites, including the major metabolites, 1- and 3-oxides and the 3- and 4-hydroxy derivatives. The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not a substrate of P-glycoprotein. Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole. Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION section). Detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. During administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 µg/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 µg/mL and 68.0 µg/mL, respectively. These steady-state levels were achieved after three days of drug administration.1 Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N4-acetylated metabolite.2 When administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middle ear fluid; trimethoprim also distributes to bronchial secretion, and both pass the placental barrier and are excreted in human milk. Geriatric Pharmacokinetics: The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-US approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, Rev 13, June 2013 Reference ID: 3339935 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects.3 Microbiology Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria. In vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone. Sulfamethoxazole and trimethoprim have been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobic gram-positive microorganisms: Streptococcus pneumoniae Aerobic gram-negative microorganisms: Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler’s diarrhea) Klebsiella species Enterobacter species Haemophilus influenzae Morganella morganii Proteus mirabilis Proteus vulgaris Shigella flexneri Shigella sonnei Other Organisms: Pneumocystis jiroveci Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar)4,15. The MIC values should be interpreted according to the criteria provided in Table 1. Rev 13, June 2013 Reference ID: 3339935 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method14,15. This procedure uses paper disks impregnated with 1.25/23.75 µg of trimethoprim/sulfamethoxazole to test the susceptibility of microorganisms to trimethoprim/sulfamethoxazole. The disc diffusion interpretive criteria are provided in Table 1. Table 1: Susceptibility Test Interpretive Criteria for Trimethoprim/Sulfamethoxazole Bacteria Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) S I R S I R Enterobacteriaceae ≤ 2/38 - ≥ 4/76 ≥ 16 11 – 15 ≤ 10 Haemophilus influenzae ≤ 0.5/9.5 1/19 – 2/38 ≥ 4/76 ≥ 16 11 – 15 ≤ 10 Streptococcus pneumoniae ≤ 0.5/9.5 1/19 – 2/38 ≥ 4/76 ≥ 19 16 – 18 ≤ 15 A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay and the techniques of the individuals performing the test4, 14, 15. Standard trimethoprim/sulfamethoxazole powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 1.25/23.75 µg trimethoprim/sulfamethoxazole disk the criteria in Table 2 should be achieved. Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Trimethoprim/Sulfamethoxazole QC Strain Minimal Inhibitory Zone Diameter Concentration (mm) (mcg/mL) Escherichia coli ATCC 25922 ≤ 0.5/9.5 23–29 Haemophilus influenzae ATCC 49247 0.03/0.59 – 0.25/4.75 24–32 Streptococcus pneumoniae ATCC 49619 0.12/2.4 – 1/19 20–28 Rev 13, June 2013 Reference ID: 3339935 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bactrim (sulfamethoxazole and trimethoprim) tablets and other antibacterial drugs, Bactrim (sulfamethoxazole and trimethoprim) tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to empiric selection of therapy. Urinary Tract Infections: For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination. Acute Otitis Media: For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of other antimicrobial agents. To date, there are limited data on the safety of repeated use of BACTRIM in pediatric patients under two years of age. BACTRIM is not indicated for prophylactic or prolonged administration in otitis media at any age. Acute Exacerbations of Chronic Bronchitis in Adults: For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when a physician deems that BACTRIM could offer some advantage over the use of a single antimicrobial agent. Shigellosis: For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated. Pneumocystis jiroveci Pneumonia: For the treatment of documented Pneumocystis jiroveci pneumonia and for prophylaxis against P. jiroveci pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing P. jiroveci pneumonia. Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea due to susceptible strains of enterotoxigenic E. coli. CONTRAINDICATIONS BACTRIM is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides, in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides, and in patients with documented megaloblastic anemia due to folate deficiency. BACTRIM is contraindicated in pediatric patients less than 2 months of age. BACTRIM is also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored. Rev 13, June 2013 Reference ID: 3339935 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Embryofetal Toxicity Some epidemiologic studies suggest that exposure to sulfamethoxazole/trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If sulfamethoxazole/trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus. Hypersensitivity and Other Fatal Reactions Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. Sulfonamides, including sulfonamide-containing products such as sulfamethoxazole/trimethoprim, should be discontinued at the first appearance of skin rash or any sign of adverse reaction. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders (see PRECAUTIONS). Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions. Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment. Thrombocytopenia Sulfamethoxazole/trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole/trimethoprim. Streptococcal Infections and Rheumatic Fever The sulfonamides should not be used for treatment of group A -hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever. Clostridium difficile associated diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BACTRIM, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Rev 13, June 2013 Reference ID: 3339935 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Adjunctive treatment with Leucovorin for Pneumocystis jiroveci pneumonia Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jiroveci pneumonia in a randomized placebo controlled trial.6 Co-administration of trimethoprim sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided. PRECAUTIONS Development of drug resistant bacteria Prescribing Bactrim (sulfamethoxazole and trimethoprim) tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Folate deficiency BACTRIM should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states) and to those with severe allergies or bronchial asthma. Hematological changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy. Hemolysis In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Hypoglycemia Cases of hypoglycemia in non-diabetic patients treated with BACTRIM are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of BACTRIM are particularly at risk. Phenylalanine metabolism Trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction. Porphyria and Hypothyroidism As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction. Use in the Treatment of and Prophylaxis for Pneumocystis jiroveci Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS): AIDS patients may not tolerate or respond to Rev 13, June 2013 Reference ID: 3339935 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BACTRIM in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with BACTRIM therapy in AIDS patients who are being treated for P. jiroveci pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of BACTRIM in non-AIDS patients. Adverse effects are generally less severe in patients receiving BACTRIM for prophylaxis. A history of mild intolerance to BACTRIM in AIDS patients does not appear to predict intolerance of subsequent secondary prophylaxis.7 However, if a patient develops skin rash or any sign of adverse reaction, therapy with BACTRIM should be reevaluated (see WARNINGS). Co-administration of BACTRIM and leucovorin should be avoided with P. jiroveci pneumonia (see WARNINGS). Electrolyte Abnormalities High dosage of trimethoprim, as used in patients with P. jiroveci pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients. Severe and symptomatic hyponatremia can occur in patients receiving BACTRIM, particularly for the treatment of P. jiroveci pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications. During treatment, adequate fluid intake and urinary output should be ensured to prevent crystalluria. Patients who are “slow acetylators” may be more prone to idiosyncratic reactions to sulfonamides. Information for Patients: Patients should be counseled that antibacterial drugs including Bactrim (sulfamethoxazole and trimethoprim) tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Bactrim (sulfamethoxazole and trimethoprim) tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Bactrim (sulfamethoxazole and trimethoprim) tablets or other antibacterial drugs in the future. Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Rev 13, June 2013 Reference ID: 3339935 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests: Complete blood counts should be done frequently in patients receiving BACTRIM; if a significant reduction in the count of any formed blood element is noted, BACTRIM should be discontinued. Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function. Drug Interactions: Potential for BACTRIM to Affect Other Drugs Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Caution is recommended when Bactrim is co-administered with drugs that are substrates of CYP2C8 and 2C9 or OCT2. In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. It has been reported that BACTRIM may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when BACTRIM is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. BACTRIM may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). BACTRIM, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. There have been reports of marked but reversible nephrotoxicity with coadministration of BACTRIM and cyclosporine in renal transplant recipients. Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. Serum digoxin levels should be monitored. Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin. Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if BACTRIM is prescribed. The efficacy of tricyclic antidepressants can decrease when coadministered with BACTRIM. BACTRIM potentiates the effect of oral hypoglycemics that are metabolized by CYP2C8 (e.g., pioglitazone, repaglinide, and rosiglitazone) or CYP2C9 (e.g., glipizide and glyburide) or eliminated renally via OCT2 (e.g., metformin). Additional monitoring of blood glucose may be warranted. Rev 13, June 2013 Reference ID: 3339935 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole/trimethoprim and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine and metformin, have also been reported. In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole/trimethoprim and an angiotensin converting enzyme inhibitor.8,9 Drug/Laboratory Test Interactions: BACTRIM, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA). The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2.4-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole b.i.d.). Mutagenesis: In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities. Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro micronucleus assays using cultured human lymphocytes. Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes, trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded. Impairment of Fertility: No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim, doses roughly two times the recommended human daily dose on a body surface area basis. Pregnancy: While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or sulfamethoxazole and Rev 13, June 2013 Reference ID: 3339935 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda trimethoprim. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving sulfamethoxazole and trimethoprim. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, BACTRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratogenic Effects: Pregnancy Category D. Human Data: While there are no large prospective, well controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole/trimethoprim with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons. Alternatively, other epidemiologic studies did not detect statistically significant associations between sulfamethoxazole/trimethoprim exposure and specific malformations. Animal Data: In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area. Nonteratogenic Effects: See CONTRAINDICATIONS section. Nursing Mothers: Levels of trimethoprim/sulfamethoxazole in breast milk are approximately 2– 5% of the recommended daily dose for infants over 2 months of age. Caution should be exercised when BACTRIM is administered to a nursing woman, especially when breastfeeding, jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and kernicterus. Pediatric Use: BACTRIM is contraindicated for infants younger than 2 months of age (see INDICATIONS and CONTRAINDICATIONS sections). Geriatric Use: Clinical studies of BACTRIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Rev 13, June 2013 Reference ID: 3339935 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions (see DOSAGE AND ADMINISTRATION section). The trimethoprim component of BACTRIM may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of BACTRIM treatment is recommended to help lower potassium serum levels. Bactrim Tablets contain 1.8 mg sodium (0.08 mEq) of sodium per tablet. Bactrim DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet. Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics). ADVERSE REACTIONS The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS (SEE WARNINGS SECTION). Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia. Allergic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch- Schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported. Gastrointestinal: Hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia. Rev 13, June 2013 Reference ID: 3339935 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Genitourinary: Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine. Metabolic and Nutritional: Hyperkalemia, hyponatremia (see PRECAUTIONS: Electrolyte Abnormalities). Neurologic: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache. Psychiatric: Hallucinations, depression, apathy, nervousness. Endocrine: The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Musculoskeletal: Arthralgia and myalgia. Isolated cases of rhabdomyolysis have been reported with BACTRIM, mainly in AIDS patients. Respiratory: Cough, shortness of breath and pulmonary infiltrates (see WARNINGS). Miscellaneous: Weakness, fatigue, insomnia. Postmarketing Experience The following adverse reactions have been identified during post-approval use of trimethoprim sulfamethoxazole. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure:  Thrombotic thrombocytopenia purpura  Idiopathic thrombocytopenic purpura  QT prolongation resulting in ventricular tachycardia and torsade de pointes OVERDOSAGE Acute: The amount of a single dose of BACTRIM that is either associated with symptoms of overdosage or is likely to be life-threatening has not been reported. Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria may be noted. Blood dyscrasias and jaundice are potential late manifestations of overdosage. Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression. General principles of treatment include the institution of gastric lavage or emesis, forcing oral fluids, and the administration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient Rev 13, June 2013 Reference ID: 3339935 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating sulfamethoxazole and trimethoprim. Chronic: Use of BACTRIM at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin 5 to 15 mg daily until normal hematopoiesis is restored. DOSAGE AND ADMINISTRATION BACTRIM is contraindicated in pediatric patients less than 2 months of age. Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children: Adults: The usual adult dosage in the treatment of urinary tract infections is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. Children: The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given in two divided doses every 12 hours for 10 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. The following table is a guideline for the attainment of this dosage: Children 2 months of age or older: Weight Dose–every 12 hours lb kg Tablets 22 10 – 44 20 1 66 30 1½ 88 40 2 or 1 DS tablet For Patients with Impaired Renal Function: When renal function is impaired, a reduced dosage should be employed using the following table: Creatinine Recommended Clearance (mL/min) Dosage Regimen Above 30 Usual standard regimen 15–30 ½ the usual regimen Below 15 Use not recommended Acute Exacerbations of Chronic Bronchitis in Adults: The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 14 days. Rev 13, June 2013 Reference ID: 3339935 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pneumocystis Jiroveci Pneumonia: Treatment: Adults and Children: The recommended dosage for treatment of patients with documented Pneumocystis jiroveci pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days.11 The following table is a guideline for the upper limit of this dosage: Weight Dose–every 6 hours lb kg Tablets 18 8 – 35 16 1 53 24 1½ 70 32 2 or 1 DS tablet 88 40 2½ 106 48 3 or 1½ DS tablets 141 64 4 or 2 DS tablets 176 80 5 or 2½ DS tablets For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table. Prophylaxis: Adults: The recommended dosage for prophylaxis in adults is 1 BACTRIM DS (double strength) tablet daily.12 Children: For children, the recommended dose is 750 mg/m2/day sulfamethoxazole with 150 mg/m2/day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim.13 The following table is a guideline for the attainment of this dosage in children: Body Surface Area Dose–every 12 hours (m2) Tablets 0.26 – 0.53 ½ 1.06 1 Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea, the usual adult dosage is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 5 days. Rev 13, June 2013 Reference ID: 3339935 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED BACTRIM™ TABLETS are supplied as follows: BACTRIM™ DS (double strength) TABLETS (white, oval shaped, scored) containing 160 mg trimethoprim and 800 mg sulfamethoxazole – bottles of 100 (NDC 13310-146-01) and 500 (NDC 13310-146-05). Imprint on tablets (debossed): (front) BACTRIM DS BACTRIM™ TABLETS (white, round, scored) containing 80 mg trimethoprim and 400 mg sulfamethoxazole – bottles of 100 (NDC 13310-145-01) and 500 (NDC 13310-145-05). Imprint on tablets (debossed): (front) BACTRIM Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature] DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER. REFERENCES: 1. Kremers P, Duvivier J, Heusghem C. Pharmacokinetic Studies of Co-Trimoxazole in Man after Single and Repeated Doses. J Clin Pharmacol. Feb-Mar 1974; 14:112–117. 2. Kaplan SA, et al. Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man. J Infect Dis. Nov 1973; 128 (Suppl): S547–S555. 3. Varoquaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol. 1985;20:575–581. 4. Rudoy RC, Nelson JD, Haltalin KC. Antimicrobial Agents Chemother. May 1974;5:439–443. 5. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 9th ed. CLSI document M07– A9, CLSI, Wayne, PA, 2012. 6. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994 Oct;170(4):912–7. 7. Hardy DW, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1992; 327: 1842–1848. 8. Marinella Mark A. 1999. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontol. 45:209–212. 9. Margassery, S. and B. Bastani. 2002. Life threatening hyperkalemia and acidosis secondary to trimethoprim-sulfamethoxazole treatment. J. Nephrol. 14:410–414. 10. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973; 128 (Suppl):S657–S663. 11. Masur H. Prevention and treatment of Pneumocystis pneumonia. N Engl J Med. 1992; 327: 1853–1880. 12. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR. 1992; 41(RR–4):1–11. 13. CDC Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR. 1991; 40(RR–2):1–13. 14. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 11th ed. CLSI document M02–A11, CLSI, Wayne, PA, 2012. Rev 13, June 2013 Reference ID: 3339935 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100–S23. CLSI document M100–S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013. BACTRIMTM and BACTRIMTM DS are trademarks of Hoffmann-La Roche Inc. Manufactured for: AR SCIENTIFIC, INC. Philadelphia, PA 19124 USA by: MUTUAL PHARMACEUTICAL COMPANY, INC. Philadelphia, PA 19124 USA Rev 13, June 2013 Rev 13, June 2013 Reference ID: 3339935 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:09.899489	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017377s068s073lbl.pdf', 'application_number': 17377, 'submission_type': 'SUPPL ', 'submission_number': 73}
10,981	NDA 16-324/S-031 NDA 17-391/S-014 Page 3 PRODUCT INFORMATION Imuran® (azathioprine) 50-mg Scored Tablets 100 mg (as the sodium salt) for I.V. injection, Equivalent to 100 mg azathioprine sterile lyophilized material. Rx only WARNING: Chronic immunosuppression with this purine antimetabolite increases risk of neoplasia in humans. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. See WARNINGS. DESCRIPTION: IMURAN (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration and 100-mg vials for intravenous injection. Each scored tablet contains 50 mg azathioprine and the inactive ingredients lactose, magnesium stearate, potato starch, povidone, and stearic acid. Each 100-mg vial contains azathioprine, as the sodium salt, equivalent to 100 mg azathioprine sterile lyophilized material and sodium hydroxide to adjust pH. Azathioprine is chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. The structural formula of azathioprine is: Chemical Structure It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound. Azathioprine is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. The sodium salt of azathioprine is sufficiently soluble to make a 10mg/mL water solution which is stable for 24 hours at 59° to 77°F (15° to 25°C). Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide. CLINICAL PHARMACOLOGY: Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35 S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable. See OVERDOSAGE. Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 4 urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6 TGNs) as major metabolites (See Metabolism Scheme in Figure 1). The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA. 6-MP undergoes two major inactivation routes ( Figure 1). One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). TPMT activity is controlled by a genetic polymorphism. 1,2,3 For Caucasians and African Americans, approximately 10% of the population inherit one non-functional TPMT allele (heterozygous) conferring intermediate TPMT activity, and 0.3% inherit two TPMT non-functional alleles (homozygous) for low or absent TPMT activity. Non-functional alleles are less common in Asians. TPMT activity correlates inversely with 6 TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities, leaving TPMT methylation as the only inactivation pathway. Patients with intermediate TPMT activity may be at increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN.4-9 TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing IMURAN toxicity.2, 3, 7, 8, 9 Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. See WARNINGS, PRECAUTIONS: Drug Interactions, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections. Metabolism pathway Chart Figure 1. Metabolism pathway of azathioprine: competing pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA. GMPS: Guanosine monophosphate synthetase; HGPRT: Hypoxanthine-guanine-phosphoribosyl-transferase; IMPD: Inosine monophosphate dehydrogenase; MeMP: Methylmercaptopurine; MeMPN: Methylmercaptopurine nucleotide; TGN: Thioguanine nucleotides; TIMP: Thioinosine monophosphate; TPMT: Thiopurine S-methyltransferase; TU Thiouric acid; XO: Xanthine oxidase) (Adapted from Pharmacogenomics 2002; 3:89-98; and Cancer Res 2001; 61:5810-5816.) Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The inhibition of xanthine oxidase in patients receiving allopurinol (ZYLOPRIM®) is the basis for the azathioprine dosage reduction required in these patients (see PRECAUTIONS: Drug Interactions). Proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function. Homograft Survival: The use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graft rejections or secondary responses. Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by azathioprine. These patients have subnormal responses to vaccines, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 5 low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody responses are usually normal. Immunoinflammatory Response: Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine. The mechanisms whereby azathioprine affects autoimmune diseases are not known. Azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia, which precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued. INDICATIONS AND USAGE: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms. Renal Homotransplantation: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables. The effect of IMURAN on these variables has not been tested in controlled trials. Rheumatoid Arthritis: IMURAN is indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms. Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with IMURAN. The combined use of IMURAN with disease modifying anti rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of IMURAN with these agents cannot be recommended. CONTRAINDICATIONS: IMURAN should not be given to patients who have shown hypersensitivity to the drug. IMURAN should not be used for treating rheumatoid arthritis in pregnant women. Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of neoplasia if treated with IMURAN. WARNINGS: Severe leukopenia, thrombocytopenia, macrocytic anemia, and/or pancytopenia may occur in patients being treated with IMURAN. Severe bone marrow suppression may also occur. Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing IMURAN toxicity. 2-9 (See PRECAUTIONS: Laboratory Tests). Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection. It is suggested that patients on IMURAN have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count. Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients. Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs should be considered. IMURAN is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient's risk of neoplasia. Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 6 patients who receive aggressive treatment with immunosuppressive drugs. The degree of immunosuppression is determined, not only by the immunosuppressive regimen, but also by a number of other patient factors. The number of immunosuppressive agents may not necessarily increase the risk of post-transplant lymphomas. However, transplant patients who receive multiple immunosuppressive agents may be at risk for over- immunosuppression; therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. Information is available on the spontaneous neoplasia risk in rheumatoid arthritis, and on neoplasia following immunosuppressive therapy of other autoimmune diseases. It has not been possible to define the precise risk of neoplasia due to IMURAN. The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients. However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine. Data on neoplasia in patients receiving IMURAN can be found under ADVERSE REACTIONS. IMURAN has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose;10 a reduced percentage of fertile matings occurred when animals received 5 mg/kg. 11 Pregnancy: Pregnancy Category D. IMURAN can cause fetal harm when administered to a pregnant woman. IMURAN should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of IMURAN in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. 12 IMURAN is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies. 11 Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on IMURAN. In a detailed case report, 13 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily. 14 There have been two published reports of abnormal physical findings. Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy. 15 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus. The father was on long-term azathioprine therapy. 16 Benefit versus risk must be weighed carefully before use of IMURAN in patients of reproductive potential. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant. PRECAUTIONS: General: A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of therapy with IMURAN and are reversible upon discontinuation of the drug. The reaction can recur within hours after re-challenge with a single dose of IMURAN. Information for Patients: Patients being started on IMURAN should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. They should be informed of the danger of infection while receiving IMURAN and asked to report signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient, especially when IMURAN is being administered in the presence of impaired renal function or concomitantly with allopurinol (see Drug Interactions subsection and DOSAGE AND ADMINISTRATION). Patients should be advised of the potential risks of the use of IMURAN during pregnancy and during the nursing period. The increased risk of neoplasia following therapy with IMURAN should be explained to the patient. Laboratory Tests: Complete Blood Count (CBC) Monitoring: Patients on IMURAN should have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 7 months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. TPMT Testing: It is recommended that consideration be given to either genotype or phenotype patients for TPMT. Phenotyping and genotyping methods are commercially available. The most common non-functional alleles associated with reduced levels of TPMT activity are TPMT2, TPMT3A and TPMT3C. Patients with two non-functional alleles (homozygous) have low or absent TPMT activity and those with one non-functional allele (heterozygous) have intermediate activity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. TPMT testing may also be considered in patients with abnormal CBC results that do not respond to dose reduction. Early drug discontinuation in these patients is advisable. TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections. Drug Interactions: Use with Allopurinol: One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN, to approximately 1/3 to 1/4 the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving IMURAN and allopurinol because both TPMT and XO inactivation pathways are affected. See CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections. Use with Aminosalicylates: There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with IMURAN should be done with caution. Use with Other Agents Affecting Myelopoesis: Drugs which may affect leukocyte production, including co trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients. Use with Angiotensin-Converting Enzyme Inhibitors: The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia. Use with Warfarin: IMURAN may inhibit the anticoagulant effect of warfarin. Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section. Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section. Nursing Mothers: The use of IMURAN in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. 17, 18, 19 Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and efficacy of azathioprine in pediatric patients have not been established. ADVERSE REACTIONS: The principal and potentially serious toxic effects of IMURAN are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see WARNINGS). The frequency and severity of adverse reactions depend on the dose and duration of IMURAN as well as on the patient's underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing IMURAN for rheumatoid arthritis. The relative incidences in clinical studies are summarized below: Renal Rheumatoid Toxicity Homograft Arthritis Leukopenia (any degree) >50% 28% <2500 cells/mm3 16% 5.3% Infections 20% <1% Neoplasia Lymphoma 0.5% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 8 Others 2.8% * Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg per day) was 1.8 cases per 1000 patient- years of follow-up, compared with 0.8 cases per 1000 patient-years of follow-up in those not receiving azathioprine. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined. Hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with IMURAN. Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Macrocytic anemia and/or bleeding have been reported. TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for non-functional alleles) who are at increased risk for severe, life-threatening myelosuppression from IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS: Laboratory Tests. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine.6, 20 Gastrointestinal: Nausea and vomiting may occur within the first few months of therapy with IMURAN, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of IMURAN. A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving IMURAN for panuveitis.21, 22, 23 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, IMURAN should be permanently withdrawn. Others: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, reversible interstitial pneumonitis and hepatosplenic T-cell lymphoma. OVERDOSAGE: The oral LD50s for single doses of IMURAN in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. About 30% of IMURAN is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis.24 A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg IMURAN. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose. DOSAGE AND ADMINISTRATION: TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity from IMURAN if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non functional alleles). IMURAN should be administered with caution to patients having one non-functional allele This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 9 (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction. Renal Homotransplantation: The dose of IMURAN required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. IMURAN is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. IMURAN is often initiated with the intravenous administration of the sodium salt, with subsequent use of tablets (at the same dose level) after the postoperative period. Intravenous administration of the sodium salt is indicated only in patients unable to tolerate oral medications. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of IMURAN should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal. Rheumatoid Arthritis: IMURAN is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. IMURAN may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities. Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance IMURAN has not been determined. IMURAN can be discontinued abruptly, but delayed effects are possible. Use in Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of IMURAN or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses. Parenteral Administration: Add 10 mL of Sterile Water for Injection, and swirl until a clear solution results. This solution, equivalent to 100 mg azathioprine, is for intravenous use only; it has a pH of approximately 9.6, and it should be used within 24 hours. Further dilution into sterile saline or dextrose is usually made for infusion; the final volume depends on time for the infusion, usually 30 to 60 minutes, but as short as 5 minutes and as long as 8 hours for the daily dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published.25-31 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. HOW SUPPLIED: 50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with “IMURAN” and “50” on each tablet; bottle of 100 (NDC 65483-590-10). Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light. 20-mL vial, each containing the equivalent of 100 mg azathioprine (as the sodium salt) (NDC 65483-551-01). Store at 15° to 25°C (59° to 77°F) and protect from light. The sterile, lyophilized sodium salt is yellow, and should be dissolved in Sterile Water for Injection (see DOSAGE AND ADMINISTRATION: Parenteral Administration). REFERENCES: 1. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43:329-339. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 10 2. Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos. 2001;29:601-605. 3. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3:89-98. 4. Anstey A, Lennard L, Mayou SC, et al. Pancytopenia related to azathioprine – an enzyme deficiency caused by a common genetic polymorphism: a review. JR Soc Med. 1992; 85:752-756. 5. Stolk JN, Beorbooms AM, de Abreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998; 41:1858-1866. 6. Data on file, Prometheus Laboratories Inc. 7. Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997; 126:608-614. 8. Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy- limiting severe toxicity from azathioprine. Ann Intern Med. 1998; 129:716-718. 9. Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology. 2004; 43:13-18. 10. Clark JM. The mutagenicity of azathioprine in mice, Drosophila melanogaster, and Neurospora crassa. Mutat Res. 1975; 28:87-99. 11. Data on file, Prometheus Laboratories Inc. 12. Tagatz GE, Simmons RL. Pregnancy after renal transplantation. Ann Intern Med. 1975; 82:113-114. Editorial Notes. 13. Cote' CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr. 1974; 85:324-328. 14. DeWitte DB, Buick MK, Cyran SE, et al. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. J Pediatr. 1984; 105:625-628. 15. Williamson RA, Karp LE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol. 1981; 58:247-250. 16. Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA. 1970; 211: 1854-1855. 17. Data on file, Prometheus Laboratories Inc. 18. Saarikoski S, Seppälä M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol. 1973; 115:1100-1106. 19. Coulam CB, Moyer TP, Jiang NS, et al. Breast-feeding after renal transplantation. Transplant Proc. 1982; 14: 605-609. 20. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant patients. Lancet. 1993; 341:436. 21. Read AE, Wiesner RH, LaBrecque DR, et al. Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med. 1986; 104:651-655. 22. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic veno-occlusive disease in renal transplant patients. Gastroenterology. 1986; 90:446-454. 23. Weitz H, Gokel JM, Loeshke K, et al. Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch A Pathol Anat Histol. 1982; 395:245-256. 24. Schusziarra V, Ziekursch V, Schlamp R, et al. Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol Biopharm. 1976; 14:298-302. 25. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institute of Health; 1992. US Dept of Health and Human Services. Public Health Service Publication NIH 92-2621. 26. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985; 253:1590-1592. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-031 NDA 17-391/S-014 Page 11 27. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 28. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983; 1:426-428. 29. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J for Clinicians. 1983; 33:258-263. 30. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049. 31. Yodaiken RE, Bennett D. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm, 1996; 43:1193-1204. PROMETHEUS LABORATORIES INC. Manufactured by DSM Pharmaceuticals, Inc. Greenville, NC 27834 for Prometheus Laboratories Inc. San Diego, CA 92121 May 2008 IM005G08 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:10.042383	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/016324s031,017391s014lbl.pdf', 'application_number': 17391, 'submission_type': 'SUPPL ', 'submission_number': 14}
10,979	07-19-51-797 Baxter PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container DESCRIPTION PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The nominal pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. 07-19-51-797 PLASMA-LYTE 148 Injection 1 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE 148 Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. CONTRAINDICATIONS None known WARNINGS PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 07-19-51-797 PLASMA-LYTE 148 Injection 2 PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. PRECAUTIONS General Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 07-19-51-797 PLASMA-LYTE 148 Injection 3 Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. 07-19-51-797 PLASMA-LYTE 148 Injection 4 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Drug/Laboratory Test Interactions There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving Baxter gluconate containing Plasmalyte solutions. These patients were subsequently found to be free of Aspergillus infection. Therefore, positive test results for this test in patients receiving Baxter gluconate containing Plasmalyte solutions should be interpreted cautiously and confirmed by other diagnostic methods. 07-19-51-797 PLASMA-LYTE 148 Injection 5 ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2534 1000 NDC 0338-6316-04 6E2533 500 NDC 0338-6316-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. 07-19-51-797 PLASMA-LYTE 148 Injection 6 DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 07-19-51-797 PLASMA-LYTE 148 Injection 7 Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only 071951797 07-19-51-797 Rev. December 2007 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. 07-19-51-797 PLASMA-LYTE 148 Injection 8 07-19-55-069 Baxter PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in VIAFLEX Plastic Container DESCRIPTION PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 kcal/L. The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. 07-19-55-069 PLASMA-LYTE 148 Injection 1 PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE 148 Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. CONTRAINDICATIONS None known WARNINGS PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and 07-19-55-069 PLASMA-LYTE 148 Injection 2 pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. PRECAUTIONS Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Caution must be exercised in the administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. 07-19-55-069 PLASMA-LYTE 148 Injection 3 Geriatric Use Clinical studies of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Do not administer unless solution is clear and seal is intact. Drug/Laboratory Test Interactions There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving Baxter gluconate containing Plasmalyte solutions. These patients were subsequently found to be free of Aspergillus infection. Therefore, positive test results for this test in patients receiving Baxter gluconate containing Plasmalyte solutions should be interpreted cautiously and confirmed by other diagnostic methods. ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. 07-19-55-069 PLASMA-LYTE 148 Injection 4 Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in VIAFLEX plastic containers is available as shown below: Code Size NDC (mL) 2B2534 1000 NDC 0338-0179-04 2B2533 500 NDC 0338-0179-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER Warning: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. 07-19-55-069 PLASMA-LYTE 148 Injection 5 To Add Medication Warning: Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA BAR CODE POSITION ONLY 071955069 ©Copyright 1982, 1983, 1989, 1993, Baxter Healthcare Corporation. All rights reserved 07-19-55-069 Rev. December 2007 Baxter, PLASMA-LYTE, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 07-19-55-069 PLASMA-LYTE 148 Injection 6 07-19-55-171 Baxter PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container DESCRIPTION PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide. The nominal pH is 7.4 (6.5 to 8.0). PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. 07-19-55-171 PLASMA-LYTE A Injection pH 7.4 1 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE A Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. CONTRAINDICATIONS None known WARNINGS PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 07-19-55-171 PLASMA-LYTE A Injection pH 7.4 2 PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. PRECAUTIONS General Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 07-19-55-171 PLASMA-LYTE A Injection pH 7.4 3 Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. 07-19-55-171 PLASMA-LYTE A Injection pH 7.4 4 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Drug/Laboratory Test Interactions There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving Baxter gluconate containing Plasmalyte solutions. These patients were subsequently found to be free of Aspergillus infection. Therefore, positive test results for this test in patients receiving Baxter gluconate containing Plasmalyte solutions should be interpreted cautiously and confirmed by other diagnostic methods. 07-19-55-171 PLASMA-LYTE A Injection pH 7.4 5 ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2544 1000 NDC 0338-6317-04 6E2543 500 NDC 0338-6317-03 07-19-55-171 PLASMA-LYTE A Injection pH 7.4 6 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 07-19-55-171 PLASMA-LYTE A Injection pH 7.4 7 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only 071955171 07-19-55-171 Rev. December 2007 Baxter, PLASMA-LYTE and AVIVA are trademarks of Baxter International Inc. 07-19-55-171 PLASMA-LYTE A Injection pH 7.4 8 07-19-55-071 Baxter PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in VIAFLEX Plastic Container DESCRIPTION PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0). PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 kcal/L. The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 07-19-55-071 PLASMA-LYTE A Injection pH 7.4 1 CLINICAL PHARMACOLOGY PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE A Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. CONTRAINDICATIONS None known WARNINGS PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those 07-19-55-071 PLASMA-LYTE A Injection pH 7.4 2 conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. PRECAUTIONS Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Caution must be exercised in the administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Pregnancy: Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. 07-19-55-071 PLASMA-LYTE A Injection pH 7.4 3 Pediatric Use Safety and effectiveness of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Do not administer unless solution is clear and seal is intact. Drug/Laboratory Test Interactions There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving Baxter gluconate containing Plasmalyte solutions. These patients were subsequently found to be free of Aspergillus infection. Therefore, positive test results for this test in patients receiving Baxter gluconate containing Plasmalyte solutions should be interpreted cautiously and confirmed by other diagnostic methods. ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. 07-19-55-071 PLASMA-LYTE A Injection pH 7.4 4 DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in VIAFLEX plastic containers is available as shown below: Code Size NDC (mL) 2B2544 1000 NDC 0338-0221-04 2B2543 500 NDC 0338-0221-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER Warning: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This 07-19-55-071 PLASMA-LYTE A Injection pH 7.4 5 is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Warning: Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA 07-19-55-071 PLASMA-LYTE A Injection pH 7.4 6 BAR CODE POSITION ONLY 071955071 ©Copyright 1978, 1981, 1982, 1983, 1984, 1989, 1993, 1995, Baxter Healthcare Corporation. All rights reserved. 07-19-55-071 Rev. December 2007 Baxter, PLASMA-LYTE, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 07-19-55-071 PLASMA-LYTE A Injection pH 7.4 7 07-19-51-682 Baxter PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container DESCRIPTION PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 526 mg Sodium Chloride, USP (NaCl); 502 mg Sodium Gluconate (C6H11NaO7); 368 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O), 37 mg Potassium Chloride, USP (KCl); and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The nominal pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate and 23 mEq gluconate. The osmolarity is 547 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥600 mOsmol/L) may cause vein damage. The caloric content is 190 kcal/L. 07-19-51-682 PLASMA-LYTE 148 and 5% Dextrose Injection 1 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories, or as an alkalinizing agent. 07-19-51-682 PLASMA-LYTE 148 and 5% Dextrose Injection 2 CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. 07-19-51-682 PLASMA-LYTE 148 and 5% Dextrose Injection 3 PRECAUTIONS General Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). 07-19-51-682 PLASMA-LYTE 148 and 5% Dextrose Injection 4 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. 07-19-51-682 PLASMA-LYTE 148 and 5% Dextrose Injection 5 In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Drug/Laboratory Test Interactions There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving Baxter gluconate containing Plasmalyte solutions. These patients were subsequently found to be free of Aspergillus infection. Therefore, positive test results for this test in patients receiving Baxter gluconate containing Plasmalyte solutions should be interpreted cautiously and confirmed by other diagnostic methods. ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. 07-19-51-682 PLASMA-LYTE 148 and 5% Dextrose Injection 6 DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Size (mL) Code NDC 1000 6E2584 NDC 0338-6321-04 500 6E2583 NDC 0338-6321-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be 07-19-51-682 PLASMA-LYTE 148 and 5% Dextrose Injection 7 observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 07-19-51-682 PLASMA-LYTE 148 and 5% Dextrose Injection 8 Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA BAR CODE POSITION ONLY 071951682 07-19-51-682 Rev. December 2007 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. 07-19-51-682 PLASMA-LYTE 148 and 5% Dextrose Injection 9 07-19-55-172 Baxter Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in Viaflex Plastic Container DESCRIPTION Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 526 mg Sodium Chloride, USP (NaCl); 502 mg Sodium Gluconate (C6H11NaO7); 368 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O), 37 mg Potassium Chloride, USP (KCl); and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate and 23 mEq gluconate. The osmolarity is 547 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 190 kcal/L. The Viaflex plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into 07-19-55-172 Plasma-Lyte 148 and 5% Dextrose Injection 1 the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. CLINICAL PHARMACOLOGY Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories, or as an alkalinizing agent. CONTRAINDICATIONS Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or 07-19-55-172 Plasma-Lyte 148 and 5% Dextrose Injection 2 respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. PRECAUTIONS Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Caution must be exercised in the administration of Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. 07-19-55-172 Plasma-Lyte 148 and 5% Dextrose Injection 3 Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness of Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Geriatric Use Clinical studies of Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 07-19-55-172 Plasma-Lyte 148 and 5% Dextrose Injection 4 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Do not administer unless solution is clear and seal is intact. Drug/Laboratory Test Interactions There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving Baxter gluconate containing Plasmalyte solutions. These patients were subsequently found to be free of Aspergillus infection. Therefore, positive test results for this test in patients receiving Baxter gluconate containing Plasmalyte solutions should be interpreted cautiously and confirmed by other diagnostic methods. ADVERSE REACTIONS Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. All injections in Viaflex plastic containers are intended for intravenous administration using sterile equipment. 07-19-55-172 Plasma-Lyte 148 and 5% Dextrose Injection 5 As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in Viaflex plastic containers is available as shown below: Size (mL) Code NDC 1000 2B2584 NDC 0338-0149-04 500 2B2583 NDC 0338-0149-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER Warning: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. 07-19-55-172 Plasma-Lyte 148 and 5% Dextrose Injection 6 Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Warning: Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA 07-19-55-172 Plasma-Lyte 148 and 5% Dextrose Injection 7 *BAR CODE POSITION ONLY 071955172 ©Copyright 1982, 1983, 1989, 1993, Baxter Healthcare Corporation. All rights reserved. 07-19-55-172 Rev. December 2007 Baxter, PLASMA-LYTE, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 07-19-55-172 Plasma-Lyte 148 and 5% Dextrose Injection 8	custom-source	2025-02-12T13:44:10.253471	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017451s060,017378s065lbl.pdf', 'application_number': 17378, 'submission_type': 'SUPPL ', 'submission_number': 65}
10,983	Catapres® (clonidine hydrochloride, USP) Boehringer Ingelheim Oral Antihypertensive Tablets of 0.1, 0.2 and 0.3 mg Rx only Prescribing Information DESCRIPTION Catapres® (clonidine hydrochloride, USP) is a centrally acting alpha-agonist hypotensive agent available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. The 0.1 mg tablet is equivalent to 0.087 mg of the free base. The inactive ingredients are colloidal silicon dioxide, corn starch, dibasic calcium phosphate, FD&C Yellow No. 6, gelatin, glycerin, lactose, and magnesium stearate. The Catapres 0.1 mg tablet also contains FD&C Blue No.1 and FD&C Red No.3. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula: ch em ica l s tr uc tu re of clonidine hydrochloride C9H9Cl2N3 · HCl Mol. Wt. 266.56 Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol. CLINICAL PHARMACOLOGY Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. CATAPRES tablets act relatively rapidly. The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent. Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15% to 20%) of cardiac output in the supine position with no change in the peripheral resistance: at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise. Tolerance to the antihypertensive effect may develop in some patients, necessitating a reevaluation of therapy. Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated. Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use. Pharmacokinetics The plasma level of clonidine peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver. INDICATIONS AND USAGE Catapres® (clonidine hydrochloride, USP) tablets are indicated in the treatment of hypertension. CATAPRES tablets may be employed alone or concomitantly with other antihypertensive agents. CONTRAINDICATIONS CATAPRES tablets should not be used in patients with known hypersensitivity to clonidine (see PRECAUTIONS). WARNINGS Withdrawal Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with Catapres® (clonidine hydrochloride, USP) tablets, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology. An excessive rise in blood pressure following discontinuation of CATAPRES tablets therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of CATAPRES tablets. Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication. PRECAUTIONS General In patients who have developed localized contact sensitization to Catapres-TTS® (clonidine), continuation of Catapres-TTS or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction to Catapres-TTS, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). CATAPRES tablets should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal failure. Perioperative Use Administration of CATAPRES tablets should be continued to within four hours of surgery and resumed as soon as possible thereafter. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. Information for Patients Patients should be cautioned against interruption of CATAPRES tablets therapy without their physician's advice. Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. They should also be informed that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs. Patients who wear contact lenses should be cautioned that treatment with CATAPRES tablets may cause dryness of eyes. Drug Interactions Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose. Due to a potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers and beta-blockers. Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (see Toxicology). Toxicology In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid. In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged. In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days. Carcinogenesis, Mutagenesis, Impairment of Fertility Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 or 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity. Fertility of male or female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m2 basis.) Pregnancy Teratogenic Effects: Pregnancy Category C. Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of Catapres® (clonidine hydrochloride, USP) tablets produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same time or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6-15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m2 basis) in mice and rats treated on gestation days 1-14 (lowest dose employed in the study was 500 mcg/kg). No adequate, well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers As clonidine hydrochloride is excreted in human milk, caution should be exercised when Catapres® (clonidine hydrochloride, USP) tablets are administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established in adequate and well- controlled trials (see WARNINGS, Withdrawal). ADVERSE REACTIONS Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The following less frequent adverse experiences have also been reported in patients receiving CATAPRES tablets, but in many cases patients were receiving concomitant medication and a causal relationship has not been established. Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome. Also reported were a weakly positive Coombs’ test and increased sensitivity to alcohol. Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. Central Nervous System: Agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares. Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria. Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic pseudo-obstruction), salivary gland pain, and vomiting. Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention. Hematologic: Thrombocytopenia. Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase, and weight gain. Musculoskeletal: Leg cramps and muscle or joint pain. Oro-otolaryngeal: Dryness of the nasal mucosa. Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of eyes. OVERDOSAGE Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children. There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated following recent and/or large ingestions. Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination of clonidine. The largest overdose reported to date involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/ml after 1 hour, 190 ng/ml after 1.5 hours, 370 ng/ml after 2 hours, and 120 ng/ml after 5.5 and 6.5 hours. In mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively. DOSAGE AND ADMINISTRATION Adults The dose of Catapres® (clonidine hydrochloride, USP) tablets must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration. Initial Dose 0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose. Maintenance Dose Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed. Renal Impairment Dosage must be adjusted according to the degree of impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis. HOW SUPPLIED Catapres® (clonidine hydrochloride, USP) tablets are supplied as follows: Dose (mg) Color Marking Bottle of 100 0.1 Tan BI 6 NDC 0597-0006-01 0.2 Orange BI 7 NDC 0597-0007-01 0.3 Peach BI 11 NDC 0597-0011-01 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Manufactured by: Boehringer Ingelheim Promeco S.A. de C.V., Mexico City, Mexico Licensed from: Boehringer Ingelheim International GmbH Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY. ©Copyright Boehringer Ingelheim International GmbH 2009 ALL RIGHTS RESERVED Printed in USA Rev: October 2009 OT6000DJ2109 090340066/US/5	custom-source	2025-02-12T13:44:10.325632	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017407s034lbl.pdf', 'application_number': 17407, 'submission_type': 'SUPPL ', 'submission_number': 34}
10,980	NDA 16-324/S-030 NDA 17-391/S-013 Page 3 PRODUCT INFORMATION IMURAN® (azathioprine) 518700 50-mg Scored Tablets 517700 100 mg (as the sodium salt) for I.V. injection, equivalent to 100 mg azathioprine sterile lyophilized material. Rx only WARNING: Chronic immunosuppression with this purine antimetabolite increases risk of neoplasia in humans. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. See WARNINGS. DESCRIPTION: IMURAN (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration and 100-mg vials for intravenous injection. Each scored tablet contains 50 mg azathioprine and the inactive ingredients lactose, magnesium stearate, potato starch, povidone, and stearic acid. Each 100-mg vial contains azathioprine, as the sodium salt, equivalent to 100 mg azathioprine sterile lyophilized material and sodium hydroxide to adjust pH. Azathioprine is chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. The structural formula of azathioprine is: It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound. Azathioprine is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. The sodium salt of azathioprine is sufficiently soluble to make a 10mg/mL water solution which is stable for 24 hours at 59° to 77°F (15° to 25°C). Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide. CLINICAL PHARMACOLOGY: Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable. See OVERDOSAGE. Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-030 NDA 17-391/S-013 Page 4 multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites (See Metabolism Scheme in Figure 1). The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA. 6-MP undergoes two major inactivation routes (Figure 1). One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6- MeMP). TPMT activity is controlled by a genetic polymorphism.1, 2, 3 For Caucasians and African Americans, approximately 10% of the population inherit one non-functional TPMT allele (heterozygous) conferring intermediate TPMT activity, and 0.3% inherit two TPMT non-functional alleles (homozygous) for low or absent TPMT activity. Non-functional alleles are less common in Asians. TPMT activity correlates inversely with 6- TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities, leaving TPMT methylation as the only inactivation pathway. Patients with intermediate TPMT activity may be at increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN. 4-9 TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing IMURAN toxicity.2, 3, 7, 8, 9 Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. See WARNINGS, PRECAUTIONS: Drug Interactions, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections. Azathioprine 6-MP 6-MeMP inactive 6-TU inactive TIMP TPMT XO HGPRT TPMT 6-MeMPN inhibition of de novo purine synthesis 6-TGN incorporation into DNA IMPD GMPS Several kinases Figure 1. Metabolism pathway of azathioprine: competing pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA. GMPS: Guanosine monophosphate synthetase; HGPRT: Hypoxanthine-guanine-phosphoribosyl-transferase; IMPD: Inosine monophosphate dehydrogenase; MeMP: Methylmercaptopurine; MeMPN: Methylmercaptopurine nucleotide; TGN: Thioguanine nucleotides; TIMP: Thioinosine monophosphate; TPMT: Thiopurine S- methyltransferase; TU: Thiouric acid; XO: Xanthine oxidase) (Adapted from Pharmacogenomics 2002; 3:89-98; and Cancer Res 2001; 61:5810-5816.) Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The inhibition of xanthine oxidase in patients receiving allopurinol (ZYLOPRIM®) is the basis for the azathioprine dosage reduction required in these patients (see PRECAUTIONS: Drug Interactions). Proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function. Homograft Survival: The use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-030 NDA 17-391/S-013 Page 5 causes variable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graft rejections or secondary responses. Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by azathioprine. These patients have subnormal responses to vaccines, low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody responses are usually normal. Immunoinflammatory Response: Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine. The mechanisms whereby azathioprine affects autoimmune diseases are not known. Azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia, which precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued. INDICATIONS AND USAGE: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms. Renal Homotransplantation: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables. The effect of IMURAN on these variables has not been tested in controlled trials. Rheumatoid Arthritis: IMURAN is indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms. Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with IMURAN. The combined use of IMURAN with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of IMURAN with these agents cannot be recommended. CONTRAINDICATIONS: IMURAN should not be given to patients who have shown hypersensitivity to the drug. IMURAN should not be used for treating rheumatoid arthritis in pregnant women. Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of neoplasia if treated with IMURAN. WARNINGS: Severe leukopenia, thrombocytopenia, macrocytic anemia, and/or pancytopenia may occur in patients being treated with IMURAN. Severe bone marrow suppression may also occur. Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing IMURAN toxicity.2-9 See PRECAUTIONS: Laboratory Tests. Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection. It is suggested that patients on IMURAN have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-030 NDA 17-391/S-013 Page 6 Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients. Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs should be considered. IMURAN is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient’s risk of neoplasia. Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs. The degree of immunosuppression is determined, not only by the immunosuppressive regimen, but also by a number of other patient factors. The number of immunosuppressive agents may not necessarily increase the risk of post-transplant lymphomas. However, transplant patients who receive multiple immunosuppressive agents may be at risk for over-immunosuppression; therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. Information is available on the spontaneous neoplasia risk in rheumatoid arthritis, and on neoplasia following immunosuppressive therapy of other autoimmune diseases. It has not been possible to define the precise risk of neoplasia due to IMURAN. The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients. However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine. Data on neoplasia in patients receiving IMURAN can be found under ADVERSE REACTIONS. IMURAN has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose;10 a reduced percentage of fertile matings occurred when animals received 5 mg/kg. 11 Pregnancy: Pregnancy Category D. IMURAN can cause fetal harm when administered to a pregnant woman. IMURAN should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of IMURAN in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. 12 IMURAN is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies. 11 Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on IMURAN. In a detailed case report, 13 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily. 14 There have been two published reports of abnormal physical findings. Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy. 15 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus. The father was on long-term azathioprine therapy. 16 Benefit versus risk must be weighed carefully before use of IMURAN in patients of reproductive potential. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant. PRECAUTIONS: General: A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of therapy with IMURAN and are reversible upon discontinuation of the drug. The reaction can recur within hours after re- challenge with a single dose of IMURAN. Information for Patients: Patients being started on IMURAN should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. They should be informed of the danger of infection while receiving IMURAN and asked to report signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient, especially when IMURAN is being This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-030 NDA 17-391/S-013 Page 7 administered in the presence of impaired renal function or concomitantly with allopurinol (see Drug Interactions subsection and DOSAGE AND ADMINISTRATION). Patients should be advised of the potential risks of the use of IMURAN during pregnancy and during the nursing period. The increased risk of neoplasia following therapy with IMURAN should be explained to the patient. Laboratory Tests: Complete Blood Count (CBC) Monitoring: Patients on IMURAN should have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. TPMT Testing: It is recommended that consideration be given to either genotype or phenotype patients for TPMT. Phenotyping and genotyping methods are commercially available. The most common non-functional alleles associated with reduced levels of TPMT activity are TPMT2, TPMT3A and TPMT3C. Patients with two non-functional alleles (homozygous) have low or absent TPMT activity and those with one non-functional allele (heterozygous) have intermediate activity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. TPMT testing may also be considered in patients with abnormal CBC results that do not respond to dose reduction. Early drug discontinuation in these patients is advisable. TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections. Drug Interactions: Use with Allopurinol: One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN, to approximately 1/3 to 1/4 the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving IMURAN and allopurinol because both TPMT and XO inactivation pathways are affected. See CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS:Laboratory Tests and ADVERSE REACTIONS sections. Use with Aminosalicylates: There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with IMURAN should be done with caution. Use with Other Agents Affecting Myelopoesis: Drugs which may affect leukocyte production, including co- trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients. Use with Angiotensin-Converting Enzyme Inhibitors: The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia. Use with Warfarin: IMURAN may inhibit the anticoagulant effect of warfarin. Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section. Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section. Nursing Mothers: The use of IMURAN in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. 17, 18, 19 Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and efficacy of azathioprine in pediatric patients have not been established. ADVERSE REACTIONS: The principal and potentially serious toxic effects of IMURAN are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see WARNINGS). The frequency and severity of adverse reactions depend on the dose and duration of IMURAN as well as on the patient’s underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing IMURAN for rheumatoid arthritis. The relative incidences in clinical studies are summarized below: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-030 NDA 17-391/S-013 Page 8 Toxicity Renal Homograft Rheumatoid Arthritis Leukopenia (any degree) >50% 28% <2500 cells/mm3 16% 5.3% Infections 20% <1% Neoplasia Lymphoma Others 0.5% 2.8% * Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg per day) was 1.8 cases per 1000 patient-years of follow-up, compared with 0.8 cases per 1000 patient-years of follow-up in those not receiving azathioprine. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined. Hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with IMURAN. Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Macrocytic anemia and/or bleeding have been reported. TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for non- functional alleles) who are at increased risk for severe, life-threatening myelosuppression from IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS:Laboratory Tests. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine. 6, 20 Gastrointestinal: Nausea and vomiting may occur within the first few months of therapy with IMURAN, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of IMURAN. A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving IMURAN for panuveitis.21, 22, 23 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, IMURAN should be permanently withdrawn. Others: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, and reversible interstitial pneumonitis. OVERDOSAGE: The oral LD50s for single doses of IMURAN in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. About 30% of IMURAN is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis.24 A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg IMURAN. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-030 NDA 17-391/S-013 Page 9 DOSAGE AND ADMINISTRATION: TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity are at an increased risk of developing severe, life- threatening myelotoxicity from IMURAN if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non-functional alleles). IMURAN should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction. Renal Homotransplantation: The dose of IMURAN required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. IMURAN is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. IMURAN is often initiated with the intravenous administration of the sodium salt, with subsequent use of tablets (at the same dose level) after the postoperative period. Intravenous administration of the sodium salt is indicated only in patients unable to tolerate oral medications. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of IMURAN should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal. Rheumatoid Arthritis: IMURAN is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. IMURAN may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities. Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance IMURAN has not been determined. IMURAN can be discontinued abruptly, but delayed effects are possible. Use in Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of IMURAN or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses. Parenteral Administration: Add 10 mL of Sterile Water for Injection, and swirl until a clear solution results. This solution, equivalent to 100 mg azathioprine, is for intravenous use only; it has a pH of approximately 9.6, and it should be used within 24 hours. Further dilution into sterile saline or dextrose is usually made for infusion; the final volume depends on time for the infusion, usually 30 to 60 minutes, but as short as 5 minutes and as long as 8 hours for the daily dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published.25-31 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. HOW SUPPLIED: 50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with “IMURAN” and “50” on each tablet; bottle of 100 (NDC 65483-590-10). Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light. 20-mL vial, each containing the equivalent of 100 mg azathioprine (as the sodium salt) (NDC 65483-551-01). Store at 15° to 25°C (59° to 77°F) and protect from light. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-030 NDA 17-391/S-013 Page 10 The sterile, lyophilized sodium salt is yellow, and should be dissolved in Sterile Water for Injection (see DOSAGE AND ADMINISTRATION: Parenteral Administration). REFERENCES: 1. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43:329-339. 2. Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos. 2001;29:601-605. 3. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3:89-98. 4. Anstey A, Lennard L, Mayou SC, et al. Pancytopenia related to azathioprine – an enzyme deficiency caused by a common genetic polymorphism: a review. JR Soc Med. 1992; 85:752-756. 5. Stolk JN, Beorbooms AM, de Abreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998; 41:1858-1866. 6. Data on file, Prometheus Laboratories Inc. 7. Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997; 126:608-614. 8. Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med. 1998; 129:716-718. 9. Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology. 2004; 43:13-18. 10. Clark JM. The mutagenicity of azathioprine in mice, Drosophila melanogaster, and Neurospora crassa. Mutat Res. 1975; 28:87-99. 11. Data on file, Prometheus Laboratories Inc. 12. Tagatz GE, Simmons RL. Pregnancy after renal transplantation. Ann Intern Med. 1975; 82:113-114. Editorial Notes. 13. Cote’ CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr. 1974; 85:324-328. 14. DeWitte DB, Buick MK, Cyran SE, et al. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. J Pediatr. 1984; 105:625-628. 15. Williamson RA, Karp LE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol. 1981; 58:247-250. 16. Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA. 1970; 211: 1854-1855. 17. Data on file, Prometheus Laboratories Inc. 18. Saarikoski S, Seppälä M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol. 1973; 115:1100-1106. 19. Coulam CB, Moyer TP, Jiang NS, et al. Breast-feeding after renal transplantation. Transplant Proc. 1982; 14: 605-609. 20. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant patients. Lancet. 1993; 341:436. 21. Read AE, Wiesner RH, LaBrecque DR, et al. Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med. 1986; 104:651-655. 22. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic veno-occlusive disease in renal transplant patients. Gastroenterology. 1986; 90:446-454. 23. Weitz H, Gokel JM, Loeshke K, et al. Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch A Pathol Anat Histol. 1982; 395:245-256. 24. Schusziarra V, Ziekursch V, Schlamp R, et al. Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol Biopharm. 1976; 14:298-302. 25. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institute of Health; 1992. US Dept of Health and Human Services. Public Health Service Publication NIH 92-2621. 26. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985; 253:1590-1592. 27. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 28. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983; 1:426-428. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 16-324/S-030 NDA 17-391/S-013 Page 11 29. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J for Clinicians. 1983; 33:258-263. 30. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049. 31. Yodaiken RE, Bennett D. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm, 1996; 43:1193-1204. PROMETHEUS LABORATORIES INC. Manufactured by DSM Pharmaceuticals, Inc. Greenville, NC 27834 for Prometheus Laboratories Inc. San Diego, CA 92121 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:10.327202	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/016324s030,017391s013lbl.pdf', 'application_number': 17391, 'submission_type': 'SUPPL ', 'submission_number': 13}
10,982	NDA 17-398/S-015 Page 3 PACKAGE INSERT REGONOL® (pyridostigmine bromide injection USP) CONTAINS BENZYL ALCOHOL THIS DRUG SHOULD BE ADMINISTERED BY ADEQUATELY TRAINED INDIVIDUALS FAMILIAR WITH ITS ACTIONS, CHARACTERISTICS, AND HAZARDS. DESCRIPTION REGONOL® (pyridostigmine bromide injection USP) is an active cholinesterase inhibitor chemically designated as 3-hydroxy-1- methylpyridinium bromide dimethyl-carbamate. Its structural formula is: REGONOL® is supplied as a sterile, isotonic, nonpyrogenic solution for injection. Each mL contains 5 mg of pyridostigmine bromide with 1% BENZYL ALCOHOL, WHICH IS NOT INTENDED FOR USE IN NEWBORNS, as the preservative. The pH is buffered with sodium citrate and citric acid and adjusted with sodium hydroxide if necessary. CLINICAL PHARMACOLOGY REGONOL® (pyridostigmine bromide injection USP), an analogue of neostigmine, facilitates the transmission of impulses across the myoneural junction by inhibiting the destruction of acetylcholine by cholinesterase. Currently available data indicate that pyridostigmine may have a significantly lower degree and incidence of bradycardia, salivation and gastrointestinal stimulation than does neostigmine. Animal studies using the injectable form of pyridostigmine and human studies using the oral preparation have indicated that pyridostigmine has a longer duration of action than does neostigmine measured under similar circumstances.1,2 REGONOL® is effective in reversing the neuromuscular blocking effects of nondepolarizing muscle relaxants. Anticholinesterase agents such as REGONOL® and neostigmine may produce depolarization block when administered at doses above their recommended therapeutic ranges. The therapeutic index of REGONOL® (ratio of reversal dose to blocking dose) is approximately 1:6 (See OVERDOSAGE).3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-398/S-015 Page 4 The antagonism of neuromuscular blockade by anticholinesterase agents may be influenced by the degree of spontaneous recovery achieved when the reversal agent is administered, by the particular relaxant administered, acid-base balance, body temperature, electrolyte imbalance, concomitant medications such as potent inhalational anesthetics, antibiotics or other drugs which enhance or antagonize the action of nondepolarizing muscle relaxants.4 The use of peripheral nerve stimulation to determine the degree of neuromuscular blockade is recommended in evaluating the effects of the reversal agents. Failure of anticholinesterase agents to produce prompt (within 30 minutes) reversal of neuromuscular blockade may occur in the presence of extreme debilitation, carcinomatosis, and with concomitant use of certain broad-spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or cause respiratory depression through their own pharmacologic actions. As with other anticholinesterase agents, the administration of REGONOL® may be associated with muscarinic and nicotinic side effects, notably bradycardia and excessive bronchial secretions; the use of glycopyrrolate or atropine sulfate simultaneously with or prior to administration of REGONOL® is recommended to counteract these side effects (See DOSAGE AND ADMINISTRATION).5 Pharmacokinetics It has been postulated that the clearance of pyridostigmine is almost equally dependent on metabolism and on urinary elimination of the unchanged drug.6 Other studies in man indicated that approximately 75 percent of the plasma clearance of pyridostigmine is dependent on renal excretion and the remainder on nonrenal mechanisms.7 INDICATIONS AND USAGE REGONOL® (pyridostigmine bromide injection USP) is indicated as a reversal agent or antagonist to the neuromuscular blocking effects of nondepolarizing muscle relaxants. CONTRAINDICATIONS Known hypersensitivity to anticholinesterase agents; intestinal and urinary obstructions of mechanical type. WARNINGS NOT FOR USE IN NEONATES REGONOL® (pyridostigmine bromide injection USP) should be used with particular caution in patients with bronchial asthma or cardiac dysrhythmias. Transient bradycardia may occur and be relieved by atropine sulfate. Atropine sulfate should also be used with caution in patients with cardiac dysrhythmias. When large doses of pyridostigmine bromide are administered, as during reversal of muscle relaxants, prior or simultaneous injection of atropine sulfate or an equipotent dose of glycopyrrolate is advisable. Because of the possibility of hypersensitivity in an occasional patient, atropine and antishock medication should always be readily available. When used as an antagonist to nondepolarizing muscle relaxants, adequate recovery of voluntary respiration and neuromuscular transmission must be obtained prior to discontinuation of respiratory assistance, and there should be continuous patient observation. Satisfactory recovery may be judged by This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-398/S-015 Page 5 adequacy of skeletal muscle tone, respiratory measurements, and by observation of the response to peripheral nerve stimulation. A patent airway should be maintained and manual or mechanical ventilation should be continued until complete recovery of normal respiration is assured. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (See PRECAUTIONS, Pediatric Use). PRECAUTIONS THE USE OF A PERIPHERAL NERVE STIMULATOR TO MONITOR RECOVERY OF NEUROMUSCULAR FUNCTION WILL MINIMIZE THE POSSIBILITY OF EXCESS DOSING OR INADEQUATE REVERSAL. Inadequate reversal of the neuromuscular blockade induced by nondepolarizing (curariform) muscle relaxants is possible. This can be managed by manual or mechanical ventilation until recovery is judged adequate. The administration of additional doses of anticholinesterase reversal agents is not recommended since excessive dosages of such drugs may produce depolarizing block through their own pharmacologic actions. Pyridostigmine is mainly excreted unchanged by the kidney.2,7,8 Therefore, lower doses may be required in patients with renal disease, and treatment should be based on titration of drug dosage to effect.2,7 Drug Interactions Concomitant administration of REGONOL® (pyridostigmine bromide injection USP) and 4- aminopyridine has been reported to delay the onset of action of REGONOL®.9 Antibiotics: Parenteral administration of high doses of certain antibiotics may intensify or produce neuromuscular block through their own pharmacologic actions. The following antibiotics have been associated with various degrees of paralysis: aminoglycosides (such as neomycin, streptomycin, kanamycin, gentamicin, and dihydrostreptomycin); tetracyclines; bacitracin; polymyxin B; colistin; and sodium colistimethate. If these or other newly introduced antibiotics are used in conjunction with nondepolarizing neuromuscular blocking drugs during surgery, unexpected prolongation of neuromuscular block or resistance to its reversal should be considered a possibility. Other: Experience concerning injection of quinidine during recovery from use of nondepolarizing muscle relaxants suggest that recurrent paralysis may occur. This possibility must be considered when administering anticholinesterase agents to antagonize neuromuscular blockade induced by nondepolarizing muscle relaxants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-398/S-015 Page 6 Electrolyte imbalance and diseases which lead to electrolyte imbalance, such as adrenal cortical insufficiency, have been shown to alter neuromuscular blockade. Depending on the nature of the imbalance, either enhancement or inhibition may be expected. Magnesium salts, administered for the management of toxemia of pregnancy, may enhance the neuromuscular blockade. The possibility that such circumstances may interfere with the restoration of neuromuscular function should be considered when administering REGONOL®. Interactions with Laboratory Tests None known. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential or impairment of fertility. Pregnancy Category C: It is not known whether REGONOL® (pyridostigmine bromide injection USP) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. REGONOL® should be given to a pregnant woman only if the administering clinician decides that the benefits outweigh the risks. Pediatric Use Safety and efficacy in pediatric patients have not been established. Benzyl alcohol, a component of this drug product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. ADVERSE REACTIONS The side effects of pyridostigmine bromide are most commonly related to overdosage and generally are of two varieties, muscarinic and nicotinic. Among those in the former group are nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, increased bronchial secretions, miosis, and diaphoresis. Nicotinic side effects are comprised chiefly of muscle cramps, fasciculation, and weakness. Muscarinic side effects can usually be counteracted by atropine. As with any compound containing the bromide radical, a skin rash may be seen in an occasional patient. Such reactions usually subside promptly upon discontinuance of the medication. Thrombophlebitis has been reported subsequent to intravenous administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-398/S-015 Page 7 OVERDOSAGE THE POSSIBILITY OF IATROGENIC OVERDOSAGE CAN BE MINIMIZED BY CAREFULLY MONITORING THE MUSCLE TWITCH RESPONSE TO PERIPHERAL NERVE STIMULATION. Should overdosage occur, ventilation should be supported by artificial means until the adequacy of spontaneous respiration is assured, and cardiac function should be monitored. Respiratory depression following administration of nondepolarizing neuromuscular blocking agents may be due either wholly or in part to other drugs used during the conduct of general anesthesia, such as narcotics, thiobarbiturates and other central nervous system depressants. A peripheral nerve stimulator may be used to assess the degree of residual neuromuscular blockade and to help differentiate residual neuromuscular blockade from other causes of decreased respiratory reserve. DOSAGE AND ADMINISTRATION REGONOL® (pyridostigmine bromide injection USP) is for intravenous use only. This drug should be administered by or under the supervision of experienced clinicians familiar with the use of agents which reverse or antagonize the effects of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. NOTE: CONTAINS BENZYL ALCOHOL (See PRECAUTIONS). Reversal doses of REGONOL® range from 0.1 to 0.25 mg/kg.5,10,11,12,13 The onset time to peak effect is dose-dependent; return of twitch height to 90% of control occurs within approximately 6 minutes following administration of a 0.25 mg/kg dose of REGONOL®.5,12 At lower doses, full recovery usually occurs within 15 minutes in most patients, although others may require a half-hour or more. When REGONOL® is given intravenously to reverse the action of muscle relaxant drugs, it is recommended that atropine sulfate (0.6 to 1.2 mg) or an equipotent dose of glycopyrrolate be given immediately prior to or simultaneously with the administration of REGONOL®. Side effects, notably excessive secretions and bradycardia are thereby minimized. Please refer to the appropriate prescribing information prior to the use of glycopyrrolate or atropine sulfate. To obtain maximum clinical benefits of REGONOL® and to minimize the possibility of overdosage, the monitoring of muscle twitch response to peripheral nerve stimulation is advised. REGONOL® should be administered after spontaneous recovery of neuromuscular function has begun. Satisfactory reversal can be evident by adequate voluntary respiration, respiratory measurements and use of a peripheral nerve stimulator device. It is recommended that the patient be well-ventilated and a patent airway maintained until complete recovery of normal respiration is assured. Once satisfactory reversal has been attained following administration of REGONOL®, recurrence of paralysis is unlikely to occur. Inadequate reversal of neuromuscular blockade by anticholinesterase drugs is possible with all curariform drugs, and is managed by manual or mechanical ventilation until recovery is judged adequate. The administration of additional doses of anticholinesterase reversal agents is not This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-398/S-015 Page 8 recommended since excessive dosages of such drugs may produce depolarizing block through their own pharmacological actions. Use in Pediatrics The safety and efficacy of REGONOL® (pyridostigmine bromide injection USP) in pediatric patients have not been established, therefore no dosing recommendations can be made (See PRECAUTIONS). HOW SUPPLIED REGONOL® (pyridostigmine bromide injection USP) is available in the following: REGONOL® 2 mL ampoules, containing 10 mg pyridostigmine bromide injection (5 mg/mL). Boxes of 10 (NDC 54643-5820-0). REGONOL® 5 mL vials, containing 25 mg pyridostigmine bromide injection (5 mg/mL). Boxes of 10 (NDC 54643-5821-0). CONTAINS BENZYL ALCOHOL. Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F). Protect from light. Rx Only REFERENCES 1. -Baker PR, Calvey TN, Chan K, Macnee CM, Taylor K. Plasma clearance of neostigmine and pyridostigmine in the dog. Br J Pharmacol 1978;63:509-512. 2. -Cronnelly R, Stanski DR, Miller RD, Sheiner LB. Pyridostigmine kinetics with and without renal function. Clin Pharmacol & Ther 1980;28:78-81. 3. -Katz RL. Pyridostigmine (Mestinon) as an antagonist of d-tubocurarine. Anesthesiology 1967;28:528-534. 4. -Miller RD. Antagonism of neuromuscular blockade. Anesthesiology 1967; 44: 318-329. 5. -Gyermek L. Clinical studies on the reversal of the neuromuscular blockade produced by pancuronium bromide. 1. The effects of glycopyrrolate and pyridostigmine. Curr Ther Res 1975; 18:20-23. 6. -Williams ME, Calvey TN, Chan K. Plasma concentration of pyridostigmine during the antagonism of neuromuscular block. Br J Anesth 1983; 55:27-30. 7. -Miller RD. Pharmacodynamics and pharmacokinetics of anticholinesterase. In: Ruegheimer E, Zindler M, eds., Anaesthesiology, Amsterdam, Netherlands: Excerpta Medica 1981: 222-223. 8. -Breyer-Pfaff U, Maier U, Brinkmann AM, Schumm F. Pyridostigmine kinetics in healthy subjects and patients with myasthenia gravis. Clin Pharmacol Ther 1985;5:494-501. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-398/S-015 Page 9 9. -Miller RD, Booij LH, Agoston S, Crul JF. 4-aminopyridine potentiates neostigmine and pyridostigmine in man. Anesthesiology 1979;50:416-420. 10. -Gyermek L. The Glycopyrrolate-Pyridostigmine Combination. Anesthesiology Review 1978;5:19- 22. 11. -Zsigmond EK. New Safe and Effective Antagonist of Pancuronium Bromide: Pyridostigmine Bromide. A Scientific Exhibit Presented at the American Medical Association Annual Convention in New York City, NY; June 23-27, 1973. 12. -Rusin WD. Comparison of Neostigmine and Pyridostigmine as Antagonists of Pancuronium Neuromuscular Blockade. ASA Clinical Papers, 299-300, 1976. 13. -Katz R. Pyridostigmine as an Antagonist of d-Tubocurarine. Anesthesiology 1967;3:528-534. 14. -Miller RD, Van Nyhuis LS, Eger EI, Vitez TS, Way WL. Comparative Times to Peak Effect and Durations of Action of Neostigmine and Pyridostigmine. Anesthesiology 1974; 41:27-33. 15. -Fogdall RP, Miller RD. Antagonism of d-Tubocurarine and Pancuronium Induced Neuromuscular Blockades by Pyridostigmine in Man. Anesthesiology 1973;39:504-509. FOR DRUG INFORMATION: 1-866-577-INFO (4636) June 2003 Revised: May 2004 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:10.340572	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/17398s015lbl.pdf', 'application_number': 17398, 'submission_type': 'SUPPL ', 'submission_number': 15}
10,985	s t ru ct ura l f or mu la Catapres® (clonidine hydrochloride, USP) company logo Oral Antihypertensive Tablets of 0.1, 0.2 and 0.3 mg Rx only Prescribing Information DESCRIPTION Catapres® (clonidine hydrochloride, USP) is a centrally acting alpha-agonist hypotensive agent available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. The 0.1 mg tablet is equivalent to 0.087 mg of the free base. The inactive ingredients are colloidal silicon dioxide, corn starch, dibasic calcium phosphate, FD&C Yellow No. 6, gelatin, glycerin, lactose, and magnesium stearate. The Catapres 0.1 mg tablet also contains FD&C Blue No.1 and FD&C Red No.3. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula: C9H9Cl2N3 · HCl Mol. Wt. 266.56 Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol. CLINICAL PHARMACOLOGY Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. CATAPRES tablets act relatively rapidly. The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. Renal blood flow and glomerular Reference ID: 3138562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent. Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15% to 20%) of cardiac output in the supine position with no change in the peripheral resistance: at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise. Tolerance to the antihypertensive effect may develop in some patients, necessitating a reevaluation of therapy. Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated. Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use. Pharmacokinetics The pharmacokinetics of clonidine is dose-proportional in the range of 100 to 600 µg. The absolute bioavailability of clonidine on oral administration is 70% to 80%. Peak plasma clonidine levels are attained in approximately 1 to 3 hours. Following intravenous administration, clonidine displays biphasic disposition with a distribution half-life of about 20 minutes and an elimination half-life ranging from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Clonidine crosses the placental barrier. It has been shown to cross the blood-brain barrier in rats. Following oral administration about 40% to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver. Neither food nor the race of the patient influences the pharmacokinetics of clonidine. The antihypertensive effect is reached at plasma concentrations between about 0.2 and 2.0 ng/mL in patients with normal excretory function. A further rise in the plasma levels will not enhance the antihypertensive effect. INDICATIONS AND USAGE CATAPRES tablets are indicated in the treatment of hypertension. CATAPRES tablets may be employed alone or concomitantly with other antihypertensive agents. Reference ID: 3138562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Catapres® (clonidine hydrochloride, USP) tablets should not be used in patients with known hypersensitivity to clonidine (see PRECAUTIONS). WARNINGS Withdrawal Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with CATAPRES tablets, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology. An excessive rise in blood pressure following discontinuation of CATAPRES tablets therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of CATAPRES tablets. Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication. PRECAUTIONS General In patients who have developed localized contact sensitization to Catapres-TTS® (clonidine), continuation of Catapres-TTS or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction to Catapres-TTS, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. There are post-marketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring IV atropine, IV isoproterenol and temporary cardiac pacing while taking clonidine. Reference ID: 3138562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In hypertension caused by pheochromocytoma, no therapeutic effect of CATAPRES tablets can be expected. Perioperative Use Administration of Catapres® (clonidine hydrochloride, USP) tablets should be continued to within 4 hours of surgery and resumed as soon as possible thereafter. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. Information for Patients Patients should be cautioned against interruption of CATAPRES tablets therapy without their physician's advice. Since patients may experience a possible sedative effect, dizziness, or accommodation disorder with use of clonidine, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery. Also, inform patients that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs. Patients who wear contact lenses should be cautioned that treatment with CATAPRES tablets may cause dryness of eyes. Drug Interactions Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose. If a patient receiving clonidine is also taking neuroleptics, orthostatic regulation disturbances (e.g., orthostatic hypotension, dizziness, fatigue) may be induced or exacerbated. Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers and beta-blockers. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil. Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (see Toxicology). Based on observations in patients in a state of alcoholic delirium it has been suggested that high intravenous doses of clonidine may increase the arrhythmogenic potential (QT prolongation, ventricular fibrillation) of high intravenous doses of haloperidol. Causal relationship and relevance for clonidine oral tablets have not been established. Toxicology In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for Reference ID: 3138562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid. In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged. In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days. Carcinogenesis, Mutagenesis, Impairment of Fertility Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 or 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity. Fertility of male or female rats was unaffected by clonidine doses as high as 150 µg/kg (approximately 3 times MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 µg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m2 basis). Pregnancy Teratogenic Effects: Pregnancy Category C. Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of Catapres® (clonidine hydrochloride, USP) tablets produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same time or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6 to 15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m2 basis) in mice and rats treated on gestation days 1 to 14 (lowest dose employed in the study was 500 µg/kg). No adequate, well-controlled studies have been conducted in pregnant women. Clonidine crosses the placental barrier (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Reference ID: 3138562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda As clonidine hydrochloride is excreted in human milk, caution should be exercised when CATAPRES tablets are administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established in adequate and well- controlled trials (see WARNINGS, Withdrawal). ADVERSE REACTIONS Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The following less frequent adverse experiences have also been reported in patients receiving CATAPRES tablets, but in many cases patients were receiving concomitant medication and a causal relationship has not been established. Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome. Also reported were a weakly positive Coombs’ test and increased sensitivity to alcohol. Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. Central Nervous System: Agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares. Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria. Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic pseudo-obstruction), salivary gland pain, and vomiting. Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention. Hematologic: Thrombocytopenia. Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase, and weight gain. Musculoskeletal: Leg cramps and muscle or joint pain. Reference ID: 3138562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Oro-otolaryngeal: Dryness of the nasal mucosa. Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of eyes. OVERDOSAGE Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children. There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated following recent and/or large ingestions. Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination of clonidine. The largest overdose reported to date involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/ml after 1 hour, 190 ng/ml after 1.5 hours, 370 ng/ml after 2 hours, and 120 ng/ml after 5.5 and 6.5 hours. In mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively. DOSAGE AND ADMINISTRATION Adults The dose of Catapres® (clonidine hydrochloride, USP) tablets must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration. Initial Dose 0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose. Reference ID: 3138562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Maintenance Dose Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed. Renal Impairment Patients with renal impairment may benefit from a lower initial dose. Patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis. HOW SUPPLIED Catapres® (clonidine hydrochloride, USP) tablets are supplied as follows: Dose (mg) Color Marking Bottle of 100 0.1 Tan BI 6 NDC 0597-0006-01 0.2 Orange BI 7 NDC 0597-0007-01 0.3 Peach BI 11 NDC 0597-0011-01 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Manufactured by: Boehringer Ingelheim Promeco S.A. de C.V. Mexico City, Mexico Licensed from: Boehringer Ingelheim International GmbH Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY. Copyright 2011 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Revised: October 2011 Reference ID: 3138562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OT6000JJI22011 090340066/8 Reference ID: 3138562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:10.639673	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017407s037lbl.pdf', 'application_number': 17407, 'submission_type': 'SUPPL ', 'submission_number': 37}

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