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11,289	_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DORAL safely and effectively. See full prescribing information for DORAL. DORAL (quazepam) Tablets for oral use C-IV Initial U.S. Approval: 1985 ----------------------------RECENT MAJOR CHANGES----------------------- Dosage and Administration (2) 4/2013 Warnings and Precautions (5) 4/2013 ----------------------------INDICATIONS AND USAGE--------------------------- DORAL, a gamma-aminobutyric ( (GABAA ) agonist, is indicated for the treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. (1) ----------------------DOSAGE AND ADMINISTRATION-----------------------  Use the lowest dose effective for the patient  Recommended initial dose is 7.5 mg (2)  Split the 15 mg tablet along the score line to achieve 7.5 mg dose (2)  The elderly and debilitated may be more sensitive to benzodiazepines (2) ---------------------DOSAGE FORMS AND STRENGTHS----------------------  15 mg functionally scored tablet, oral (3) -------------------------------CONTRAINDICATIONS------------------------------  Hypersensitivity to quazepam or other benzodiazepines (4)  Established or suspected sleep apnea, or chronic pulmonary insufficiency (4) -----------------------WARNINGS AND PRECAUTIONS------------------------  CNS depressant effects: Impaired alertness and motor coordination, including risk of daytime impairment. Caution patients against driving and other activities requiring complete mental alertness (5.1)  Benzodiazepine withdrawal syndrome: avoid abrupt discontinuation in at-risk patients (5.2)  The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. (5.3)  Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.4)  Sleep driving and other complex behaviors while not fully awake. Risk increases with dose and concomitant CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes (5.5)  Worsening of depression or suicidal thinking may occur: Prescribe the least number of tablets feasible to avoid intentional overdose (5.6) ------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (>1%): drowsiness, headache, fatigue, dizziness, dry mouth, dyspepsia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Questcor Pharmaceuticals, Inc. at 1-800-465-9217 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS-------------------------------  CNS Depressants: downward dose adjustment may be necessary due to additive effects (7) -----------------------USE IN SPECIFIC POPULATIONS------------------------  Pregnancy: Based on animal data, may cause fetal harm (8.1)  Nursing Mothers: Administration of DORAL Tablets to nursing mothers is not recommended as quazepam and its metabolites are excreted in human milk. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved Medication Guide. Revised: 04/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 CNS-Depressant Effects and Daytime Impairment 5.2 Benzodiazepine Withdrawal Syndrome 5.3 Need to Evaluate for Co-morbid Disorders 5.4 Severe Anaphylactic or Anaphylactoid Reactions 5.5 Abnormal Thinking and Behavior Changes 5.6 Worsening of Depression 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse and Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Drug Interactions 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Page 1 Reference ID: 3296465 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 DORAL® (quazepam) is indicated for the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. The effectiveness of DORAL has been established in placebo-controlled clinical studies of 5 nights duration in acute and chronic insomnia. The sustained effectiveness of DORAL has been established in chronic insomnia in a sleep lab (polysomnographic) study of 28 nights duration. Because insomnia is often transient and intermittent, the prolonged administration of DORAL Tablets is generally not necessary or recommended. Since insomnia may be a symptom of several other disorders, the possibility that the complaint may be related to a condition for which there is a more specific treatment should be considered. 2 DOSAGE AND ADMINISTRATION Use the lowest dose effective for the patient, as important adverse effects of Doral are dose related. The recommended initial dose is 7.5 mg. The 7.5 mg dose can be increased to 15 mg if necessary for efficacy. The 7.5 mg dose can be achieved by splitting the 15 mg tablet along the score line. 2.2 Special populations Elderly and debilitated patients may be more sensitive to benzodiazepines. 3 DOSAGE FORMS AND STRENGTHS Tablets, 15 mg, functionally scored, capsule-shaped, light orange, slightly white speckled tablets, impressed with the product identification number 15 on one side of the tablet, and the product name (DORAL) on the other. 4 CONTRAINDICATIONS DORAL is contraindicated in patients with known hypersensitivity to quazepam or other benzodiazepines. Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of DORAL. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Patients who develop such reactions should not be rechallenged with Doral. Contraindicated in patients with established or suspected sleep apnea, or with pulmonary insufficiency. Page 2 Reference ID: 3296465 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 CNS-depressant effects and Daytime impairment Doral is a central nervous system (CNS) depressant and can impair daytime function in some patients even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of Doral may develop, patients using Doral should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness. Additive effects occur with concomitant use of other CNS depressants (e.g., other benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of Doral and concomitant CNS depressants should be considered. The potential for adverse drug interactions continues for several days following discontinuation of Doral, until serum levels of both active parent drug and psychoactive metabolites decline. Use of Doral with other sedative-hypnotics is not recommended. Alcohol generally should not be used during treatment with Doral. The risk of next-day psychomotor impairment is increased if Doral is taken with less than a full night of sleep remaining (7- to 8 hours); if higher than the recommended dose is taken; if co-administered with other CNS depressants[see Dosage and Administration (2.3)]. 5.2 Benzodiazepine Withdrawal Syndrome A withdrawal syndrome similar to that from alcohol (e.g., convulsions, tremor, abdominal and muscle cramps, vomiting, and sweating) can occur following abrupt discontinuation of Doral. The more severe withdrawal effects are usually limited to patients taking higher than recommended doses over an extended time. Abrupt discontinuation should be avoided in such patients, and the dose gradually tapered. Prescribers should monitor patients for tolerance, abuse, and dependence. Milder withdrawal symptoms (e.g., dysphoria and insomnia) can occur following abrupt discontinuation of benzodiazepines taken at therapeutic levels for short periods [See Drug Abuse and Dependence (9)]. 5.3 Need to Evaluate for Co-morbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs. Page 3 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.4 Severe Anaphylactic and Anaphylactoid Reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including DORAL. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with DORAL should not be rechallenged with the drug. 5.5 Abnormal Thinking and Behavior Changes Abnormal thinking and behavior changes have been reported in patients treated with sedative- hypnotics including Doral. Some of these changes include decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, and depersonalization. Visual and auditory hallucinations have also been reported. Amnesia, and other neuro-psychiatric symptoms may occur. Paradoxical reactions such as stimulation, agitation, increased muscle spasticity, and sleep disturbances may occur unpredictably. Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake, with amnesia for the event) have been reported with use of sedative-hypnotics. These behaviors can occur with initial treatment or in patients previously tolerant of Doral or other sedative-hypnotics. Although these behaviors can occur with use at therapeutic doses, risk is increased by higher doses or concomitant use of alcohol or other CNS depressants. Due to risk to the patient and community, Doral should be discontinued if "sleep-driving" occurs. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. 5.6 Worsening of Depression Benzodiazepines may worsen depression. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label:  CNS-depressant effects and next-day impairment [see Warnings and Precautions (5.1)]  Benzodiazepine withdrawal syndrome[see Warnings and Precautions (5.2)]  Abnormal thinking and behavior changes, and complex behaviors[see Warnings and Precautions (5.5)]  Worsening of depression[see Warnings and Precautions (5.6)] Page 4 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The table shows adverse reactions occurring at an incidence of 1% or greater in relatively short- duration, placebo-controlled clinical trials of Doral. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in actual practice. DORAL 15 mg PLACEBO NUMBER OF PATIENTS 267 268 % OF PATIENTS REPORTING Central Nervous System Daytime Drowsiness 12 3 Headache 5 2 Fatigue 2 0 Dizziness 2 <1 Autonomic Nervous System Dry Mouth 2 <1 Gastrointestinal System Dyspepsia 1 <1 A double-blind, controlled sleep laboratory study (N=30) in elderly patients compared the effects of quazepam 7.5 mg and 15 mg to that of placebo over a period of 7 days. Both the 7.5 mg and 15 mg doses appeared to be well tolerated. Caution must be used in interpreting this data due to the small size of the study. 7 DRUG INTERACTIONS Benzodiazepines, including DORAL, produce additive CNS depressant effects when co administered with ethanol or other CNS depressants (e.g. psychotropic medications, anticonvulsants, antihistamines). Downward dose adjustment of Doral and/or concomitant CNS depressants may be necessary because of additive effects. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can Page 5 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda development dependence, and subsequently withdrawal, during the postnatal period. Although administration of quazepam to pregnant animals did not indicate a risk for adverse effects on morphological development at clinically relevant doses, data for other benzodiazepines suggest the possibility of adverse developmental effects (long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines. DORAL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Developmental toxicity studies of quazepam in mice at doses up to 400 times the human dose (15 mg) revealed no major drug-related malformations. Minor fetal skeletal variations that occurred were delayed ossification of the sternum, vertebrae, distal phalanges and supraoccipital bones, at doses approximately 70 and 400 times the human dose. A developmental toxicity study of quazepam in New Zealand rabbits at doses up to approximately 130 times the human dose demonstrated no effect on fetal morphology or development of offspring. 8.3 Nursing Mothers Quazepam and its metabolites are excreted in human milk. Caution should be exercised when administering DORAL to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Doral may cause confusion and over-sedation in the elderly. Elderly patients generally should be started on a low dose of Doral and observed closely. Elderly and debilitated patients may be more sensitive to benzodiazepines, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. A double-blind controlled sleep laboratory study (N=30) compared the effects of quazepam 7.5 mg and 15 mg to that of placebo over a period of 7 days. Both the 7.5 mg and 15 mg doses appeared to be well tolerated. Caution must be used in interpreting this data due to the small size of the study. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Quazepam is classified as a Schedule IV controlled substance by federal regulation. Page 6 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda s tructural formula 9.2 Abuse and Dependence Addiction-prone individuals (e.g. history of drug addiction or alcoholism) should be under careful surveillance when receiving Doral because of increased risk of abuse and dependence. Benzodiazepine withdrawal symptoms can occur following discontinuation of Doral [see Warnings and Precautions (5.2)]. Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects. Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. 10 OVERDOSAGE Contact a poison control center for up-to-date information on the management of benzodiazepine overdose. Manifestations of Doral overdose include somnolence, confusion, and coma. General supportive measures should be employed, along with immediate gastric lavage. Dialysis is of limited value. Flumazenil may be useful, but can contribute to the appearance of neurological symptoms including convulsions. Hypotension may be treated by appropriate medical intervention. Animal experiments suggest that forced diuresis or hemodialysis are of little value in treating Doral overdose. As with the management of intentional overdose with any drug, the possibility of multiple drug ingestion should be considered. 11 DESCRIPTION DORAL contains quazepam, a trifluoroethyl benzodiazepine hypnotic agent, having the chemical name 7-chloro-5- (o-fluoro-phenyl)-1,3-dihydro-1-(2,2,2-trifluoroethyl)-2H-1,4 benzodiazepine-2-thione and the following structural formula: Page 7 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Quazepam has the empirical formula C17H11ClF4N2S, and a molecular weight of 386.8. It is a white crystalline compound, soluble in ethanol and insoluble in water. Each DORAL Tablet contains 15 mg of quazepam. The inactive ingredients for DORAL Tablets include cellulose, corn starch, FD&C Yellow No. 6 Al Lake, lactose, magnesium stearate, silicon dioxide, and sodium lauryl sulfate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Quazepam, like other central nervous system agents of the 1,4-benzodiazepine class, presumably exerts its effects by binding to stereo-specific receptors at several sites within the central nervous system (CNS). The exact mechanism of action is unknown. 12.3 Pharmacokinetics Absorption: Quazepam is rapidly (absorption half-life of about 30 minutes) and well absorbed from the gastrointestinal tract. The peak plasma concentration of quazepam is approximately 20 ng/mL after a 15 mg dose and occurs at about 2 hours. Metabolism: Quazepam, the active parent compound, is extensively metabolized in the liver; two of the plasma metabolites are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. All three compounds show CNS depressant activity. Distribution: The degree of plasma protein binding for quazepam and its two major metabolites is greater than 95%. Elimination: Following administration of 14C-quazepam, 31% of the dose appeared in the urine and 23% in the feces over five days; only trace amounts of unchanged drug were present in the urine. The mean elimination half-life of quazepam and 2-oxoquazepam is 39 hours and that of N desalkyl-2-oxoquazepam is 73 hours. Steady-state levels of quazepam and 2-oxoquazepam are attained by the seventh daily dose and that of N-desalkyl-2-oxoquazepam by the thirteenth daily dose. Special Populations: Geriatrics: The pharmacokinetics of quazepam and 2-oxoquazepam in geriatric subjects are comparable to those seen in young adults; as with desalkyl metabolites of other benzodiazepines, the elimination half-life of N-desalkyl-2-oxoquazepam in geriatric patients is about twice that of young adults. 12.4 Drug Interactions Bupropion (a CYP2B6 substrate): Co-administration of a single dose of 150 mg Bupropion Hydrochloride XL with steady state quazepam did not significantly affect the AUC and Cmax of bupropion or its primary metabolite, hydroxybupropion. Page 8 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Quazepam showed no evidence of carcinogenicity in oral carcinogenicity studies in mice and hamsters. Mutagenesis Quazepam was negative in the bacterial reverse mutation (Ames) assay and equivocal in the mouse lymphoma tk assay. Impairment of Fertility Reproduction studies in mice conducted with quazepam at doses equal to 60 and 180 times the human dose of 15 mg produced slight reductions in fertility rate. Similar reductions in fertility rate have been reported in mice dosed with other benzodiazepines, and is believed to be related to the sedative effects of these drugs at high doses. 14 CLINICAL STUDIES The effectiveness of DORAL was established in placebo-controlled clinical studies of 5 nights duration in acute and chronic insomnia. The sustained effectiveness of DORAL was established in chronic insomnia in a sleep laboratory (polysomnographic) study of 28 nights duration. In the sleep laboratory study, DORAL significantly decreased sleep latency and total wake time, and significantly increased total sleep time and percent sleep time, for one or more nights. Doral 15 mg was effective on the first night of administration. Sleep latency, total wake time and wake time after sleep onset were still decreased and percent sleep time was still increased for several nights after the drug was discontinued. Percent slow wave sleep was decreased, and REM sleep was essentially unchanged. No transient sleep disturbance, such as “rebound insomnia,” was observed after withdrawal of the drug in sleep laboratory studies in 12 patients using 15 mg doses. In outpatient studies, DORAL Tablets improved all subjective measures of sleep including sleep latency, duration of sleep, number of awakenings, occurrence of early morning awakening, and sleep quality. Some effects were evident on the first night of administration of DORAL (sleep latency, number of awakenings, and duration of sleep). A double-blind, controlled sleep laboratory study (N=30) in elderly patients compared the effects of quazepam 7.5 mg and 15 mg to that of placebo over a period of 7 days. Both the 7.5 mg and 15 mg doses appeared to be effective. Caution must be used in interpreting this data due to the small size of the study. 16 HOW SUPPLIED DORAL Tablets, 15 mg, functionally scored, capsule-shaped, light orange, slightly white speckled tablets, impressed with the product identification number 15 on one side of the tablet, and the product name (DORAL) on the other. Page 9 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 mg Bottles of 100 NDC 63004-7734-1 Store DORAL® Tablets at controlled room temperature 20°-25°C (68°-77°F). 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Inform patients about the benefits and risks of DORAL, stressing the importance of use as directed. Assist patients in understanding the Medication Guide and instruct them to read it with each prescription refill. CNS depressant Effects and Next-Day Impairment Tell patients that Doral can cause next-day impairment, even in the absence of symptoms. Caution patients against driving or engaging in other hazardous activities or activities requiring complete mental alertness when using Doral. Tell patients that daytime impairment may persist for several days following discontinuation of Doral. Withdrawal Instruct patients to contact you before stopping or decreasing the dose of Doral, because withdrawal symptoms can occur. Abnormal thinking and behavior change Instruct patients that sedative hypnotics can cause abnormal thinking and behavior change, including “sleep-driving” and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms. Severe Allergic Reactions Inform patients that severe allergic reactions can occur from Doral. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if these occur. Suicide Tell patients that Doral can worsen depression, and to immediately report any suicidal thoughts. Alcohol and other drugs Ask patients about alcohol consumption, medicines they are taking now, and drugs they may be taking without a prescription. Advise patients that alcohol generally should not be used during treatment with Doral. Pregnancy Instruct patients to inform you if they are nursing or pregnant, or may become pregnant while taking Doral. Tolerance, Abuse, and Dependence Tell patients not to increase the dose of Doral on their own, and to inform you if they believe the drug “does not work”. Page 10 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo Manufactured for: Questcor Pharmaceuticals, Inc. Hayward, CA 94545 USA phone (800) 411-3065 (510) 400-0700 fax (510) 400-0799 Manufactured by: Meda Pharmaceuticals, Inc. Somerset, NJ 08873-4120 Under license from Baker Norton Pharmaceuticals, Inc. Printed in USA. IN-1500-06 Rev. 04/13 Page 11 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE DORAL (DOR-al) (quazepam) Tablets (C-IV) Read the Medication Guide that comes with DORAL before you start 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 healthcare provider about your medical condition or treatment. What is the most important information I should know about DORAL? Doral may cause serious side effects that you may not know are happening to you. These side effects include: • sleepiness during the day • not thinking clearly • act strangely, confused, or upset  “sleep-walking” or doing other activities when you are asleep like: o eating o talking o having sex o driving a car Call your healthcare provider right away if you find out that you have done any of the above activities after taking DORAL. What is DORAL? DORAL is a prescription medicine used to treat certain types of insomnia including difficulty falling asleep, waking up often during the night, or waking up early in the morning. It is not known if DORAL is safe and effective in children. DORAL is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep DORAL in a safe place to prevent misuse and abuse. Selling or giving away DORAL 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. Who should not take DORAL? Do not take DORAL if you:  are allergic to quazepam or any of the ingredients in DORAL. See the end of this Medication Guide for a complete list of ingredients in DORAL. Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  have had an allergic reaction to other sleep medicines or sedatives such as benzodiazepines. Symptoms of a serious allergic reaction to quazepam can include: • swelling of your face, lips, and throat that may cause difficulty breathing or swallowing • nausea and vomiting • have sleep apnea, snoring, breathing or lung problems Talk to your healthcare provider before taking this medicine if you have any of these conditions. What should I tell my healthcare provider before taking DORAL? DORAL may not be right for you. Before taking DORAL, tell your healthcare provider about all of your health conditions, including if you:  have a history of depression, mental illness or, suicidal thoughts  have a history of drug or alcohol abuse or addiction  have lung disease or breathing problems  are pregnant or plan to become pregnant. It is not known if DORAL can harm your unborn baby.  are breastfeeding, or plan to breastfeed. DORAL can pass through your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take DORAL. Tell your healthcare provider about all of the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects. Do not take DORAL with other medicines that can make you sleepy unless your healthcare provider tells you to. Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist each time you get a new medicine. How should I take DORAL?  See “What is the most important information I should know about DORAL?”  Take DORAL exactly as your healthcare providers tell you to take it.  Do not stop taking DORAL without talking to your healthcare provider, drug withdrawal symptoms can happen.  DORAL comes in 15 mg tablets. Your healthcare provider may start your DORAL dose at 7.5 mg which is half a tablet. Talk to your healthcare provider or pharmacist about your dose schedule. Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • You should not drink alcohol while you are taking DORAL.  Call your healthcare provider if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problem.  If you take too much DORAL or overdose, get emergency treatment right away. What are the possible side effects of DORAL? DORAL may cause serious side effects, including:  getting out of bed while not being fully awake and doing an activity that you do not know you are doing. See “What is the most important information I should know about DORAL?”  abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.  memory loss  severe allergic reactions. Symptoms include swelling of the tongue or throat, and trouble breathing. Get emergency medical help right away if you have these symptoms after taking DORAL. Call your healthcare provider right away if you have any of the above side effects or any other side effects that worry you while using DORAL. Common side effects of DORAL include:  drowsiness  headache  feeling very tired  dizziness  dry mouth  upset stomach After you stop taking a sleep medicine, you may have symptoms for the next 1 to 2 days such as:  trouble sleeping  vomiting  nausea  stomach cramps  flushing  panic attack  lightheadedness  nervousness  uncontrolled crying  stomach area pain Tell your healthcare provider if you have any side effect that bothers you or that Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda does not go away. These are not all the possible side effects of DORAL. Ask your healthcare provider 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 DORAL?  Store at room temperature between 68°F to 77° F (20°C to 25°C).  Keep DORAL and all medicines out of the reach of children General information about the safe and effective use of Doral. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DORAL for a condition for which it was not prescribed. Do not share DORAL with other people, even if they have the same symptoms that you have. It may harm them and it is against the law. This Medication Guide summarizes the most important information about DORAL. If you would like more information about DORAL, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DORAL that is written for healthcare professionals. If you would like more information, go to http://www.DORALforsleep.com or call Questcor Pharmaceuticals at 1-800-411-3065DORAL. What are the ingredients in DORAL? Active Ingredient: quazepam Inactive Ingredients: cellulose, corn starch, FD&C Yellow No. 6 Al Lake, lactose, magnesium stearate, silicon dioxide, and sodium lauryl sulfate. Distributed by Questcor Pharmaceuticals, Inc. Hayward, CA 94545 USA This Medication Guide has been approved by the U.S. Food and Drug Administration. (IS-1500-02 Rev. 00/13 Month and year MG is approved) Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:52.722897	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018708s020s021lbl.pdf', 'application_number': 18708, 'submission_type': 'SUPPL ', 'submission_number': 20}
11,288	NITROLINGUAL PUMPSPRAY (nitroglycerin lingual spray) spray, metered INFORMATION FOR THE PATIENT Nitrolingual® Pumpspray (nitroglycerin lingual spray) 400 mcg per spray, 60 or 200 Metered Sprays Before using your Nitrolingual® Pumpspray (nitroglycerin lingual spray) 400 mcg per spray, 60 or 200 metered sprays, read carefully the following directions for use. Nitrolingual® Pumpspray is a metered dose spray which delivers 48 mg of solution containing 400 mcg of nitroglycerin with each spray. Nitroglycerin is absorbed from the tongue and surrounding mucosa producing a prompt therapeutic effect. It is best to use Nitrolingual®Pumpspray in a sitting position. How to Use Nitrolingual® Pumpspray Before using this product for the first time, the pump must be sprayed 5 times into the air (this is known as priming). The pump should be primed every 6 weeks to remain ready for use. If the product has not been used for 6 weeks, a prime of 1 spray is necessary. 1. Remove the plastic cover. 2. DO NOT SHAKE. 3. Hold the container upright with forefinger on top of the grooved button. 4. Open the mouth and bring the container as close to it as possible. 5. Press the button firmly with the forefinger to release the spray onto or under the tongue. DO NOT INHALE THE SPRAY. 6. Release button and close mouth. Avoid swallowing immediately after administering the spray. The medication should not be expectorated or the mouth rinsed for 5 to 10 minutes following administration. 7. If you require a second administration to obtain relief, repeat steps 4, 5, and 6. 8. Replace the plastic cover. usage illustration NOTE: To familiarize yourself with the product and while priming the container, actuate the spray into the air (away from yourself and others).Get the feel of your finger resting on the grooved button so that you can use the spray in the dark. DO NOT SHAKE the container before use. You may wish to keep additional pumpspray containers handy in convenient locations. page 1 of 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage During an anginal attack, one or two sprays should be administered into your mouth, preferably onto or under the tongue. Do not inhale spray. The medication should not be expectorated or the mouth rinsed for 5 to 10 minutes following administration. A spray may be repeated approximately every 3-5 minutes as needed. No more than three metered sprays are recommended within a 15-minute period. If chest pain persists, prompt medical attention is recommended. Nitrolingual® Pumpspray may be used 5 to 10 minutes prior to engaging in activities which might provoke an acute attack. There are approximately 60 or 200 metered sprays of nitroglycerin per Nitrolingual® Pumpspray bottle. However, the number of times the medication may be used is dependent on the number of sprays per use (1 or 2 sprays), and frequency of repriming. Each metered spray of Nitrolingual®Pumpspray delivers400 mcg of nitroglycerin after an initial priming of 5 sprays.The container will remain adequately primed for 6 weeks. If the medication is not used within 6 weeks, it can be adequately reprimed with 1 spray. Longer storage periods without use may require up to 5 repriming sprays. Precaution Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician. Do not share or give your medication to others, particularly those who may appear to be having chest discomfort similar to yours. Nitrolingual®Pumpspray should be used during an episode of chest pain or may be used 5 to 10 minutes prior to engaging in activities which might provoke an acute attack. Nitrolingual®Pumpspray is available in a clear glass bottle with a red plastic coating on the exterior. This plastic coating is designed to contain the glass and medication should the bottle be shattered. The transparent container can be used for continuous monitoring of the consumption. The end of the pump should be covered by the fluid level. Once fluid falls below the level of the center tube, sprays will not be adequate and the container should be replaced. As with all other sprays, there is a residual volume of fluid at the bottom of the bottle which cannot be used. Nitrolingual® Pumpspray contains 20% alcohol. Do not forcefully open or burn container. Do not spray toward flames. Keep in a safe place and out of the reach of chiIdren. Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F) [see USP Controlled Room Temperature]. logo Manufactured for Sciele™ Pharma, Inc., Atlanta, GA 30328 by G. Pohl-Boskamp GmbH & Co. KG, 25551 Hohenlockstedt, Germany. DESCRIPTION Nitroglycerin, an organic nitrate, is a vasodilator which has effects on both arteries and veins. The chemical name for nitroglycerin is 1,2,3-propanetriol trinitrate (C3H5N3O9). The compound has a molecular weight of 227.09. The chemical structure is: Chemical Structure Nitrolingual®Pumpspray (nitroglycerin lingual spray 400 mcg) is a metered dose spray containing nitroglycerin. This product delivers nitroglycerin (400 mcg per spray, 60 or 200 metered sprays) in the form of spray droplets onto or under the tongue. Inactive ingredients: medium-chain triglycerides, dehydrated alcohol, medium-chain partial glycerides, peppermint oil. CLINICAL PHARMACOLOGY The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle, producing a vasodilator effect on both peripheral arteries and veins with more prominent effects on the latter. Dilation of the post-capillary vessels, including large veins, promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure (pre-load). Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (after-load). page 2 of 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The mechanism by which nitroglycerin relieves angina pectoris is not fully understood. Myocardial oxygen consumption or demand (as measured by the pressure-rate product, tension-time index, and stroke-work index) is decreased by both the arterial and venous effects of nitroglycerin and presumably, a more favorable supply-demand ratio is achieved. While the large epicardial coronary arteries are also dilated by nitroglycerin, the extent to which this action contributes to relief of exertional angina is unclear. Nitroglycerin is rapidly metabolized in vivo, with a liver reductase enzyme having primary importance in the formation of glycerol nitrate metabolites and inorganic nitrate. Two active major metabolites, 1,2- and 1,3-dinitroglycerols, the products of hydrolysis, although less potent as vasodilators, have longer plasma half-lives than the parent compound. The dinitrates are further metabolized to mononitrates (considered biologically inactive with respect to cardiovascular effects) and ultimately glycerol and carbon dioxide. Therapeutic doses of nitroglycerin may reduce systolic, diastolic and mean arterial blood pressure. Effective coronary perfusion pressure is usually maintained, but can be compromised if blood pressure falls excessively or increased heart rate decreases diastolic filling time. Elevated central venous and pulmonary capillary wedge pressures, pulmonary vascular resistance and systemic vascular resistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly increased, presumably a reflex response to the fall in blood pressure. Cardiac index may be increased, decreased, or unchanged. Patients with elevated left ventricular filling pressure and systemic vascular resistance values in conjunction with a depressed cardiac index are likely to experience an improvement in cardiac index. On the other hand, when filling pressures and cardiac index are normal, cardiac index may be slightly reduced. In a pharmacokinetic study when a single 0.8 mg dose of Nitrolingual®Pumpspray was administered to healthy volunteers (n = 24), the mean Cmax and tmax were 1,041pg/mL • min and 7.5 minutes, respectively. Additionally, in these subjects the mean area-under-the curve (AUC) was 12,769 pg/mL • min. In a randomized, double-blind single-dose, 5-period cross-over study in 51 patients with exertional angina pectoris significant dose- related increases in exercise tolerance, time to onset of angina and ST-segment depression were seen following doses of 0.2, 0.4, 0.8 and 1.6 mg of nitroglycerin delivered by metered pumpspray as compared to placebo. Additionally the drug was well tolerated as evidenced by a profile of generally mild to moderate adverse events. INDICATIONS & USAGE Nitrolingual®Pumpspray is indicated for acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease. CONTRAINDICATIONS Allergic reactions to organic nitrates are rare. Nitroglycerin is contraindicated in patients who are allergic to it. Nitrolingual®Pumpspray is contraindicated in patients taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), as their concomitant use can cause severe hypotension. The time course and dose-dependency of this interaction are not known. WARNINGS Amplification of the vasodilatory effects of Nitrolingual®Pumpspray bycertain drugs (phosphodiesterase inhibitors) used to treat erectile dysfunction can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion. The use of any form of nitroglycerin during the early days of acute myocardial infarction requires particular attention to hemodynamic monitoring and clinical status. PRECAUTIONS: (GENERAL) Severe hypotension, particularly with upright posture, may occur even with small doses of nitroglycerin. The drug, therefore, should be used with caution in subjects who may have volume depletion from diuretic therapy or in patients who have low systolic blood pressure (e.g., below 90 mm Hg). Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin-induced hypotension. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy. Tolerance to this drug and cross-tolerance to other nitrates and nitrites may occur. Tolerance to the vascular and anti-anginal effects of nitrates has been demonstrated in clinical trials, experience through occupational exposure, and in isolated tissue experiments in the laboratory. In industrial workers continuously exposed to nitroglycerin, tolerance clearly occurs. Moreover, physical dependence also occurs since chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitroglycerin from the page 3 of 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda workers. In various clinical trials in angina patients, there are reports of anginal attacks being more easily provoked and of rebound in the hemodynamic effects soon after nitrate withdrawal. The relative importance of these observations to the routine, clinical use of nitroglycerin is not known. PRECAUTIONS: INFORMATION FOR PATIENTS Physicians should discuss with patients that Nitrolingual®Pumpspray should not be used with certain drugs taken for erectile dysfunction (phosphodiesterase inhibitors) because of the risk of lowering their blood pressure dangerously. DRUG INTERACTIONS: Alcohol may enhance sensitivity to the hypotensive effects of nitrates. Nitroglycerin acts directly on vascular muscle. Therefore, any other agents that depend on vascular smooth muscle as the final common path can be expected to have decreased or increased effect depending upon the agent. Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and oral controlled-release nitroglycerin were used in combination. Dose adjustments of either class of agents may be necessary. Concomitant use of nitric oxide donors (like Nitrolingual®Pumpspray) and certain drugs for the treatment of erectile dysfunction (phosphodiesterase inhibitors) can amplify their vasodilatory effects, resulting in severe hypotension. The concomitant use of these drugs is contraindicated (see CONTRAINDICATIONS) and alternative therapies should be used to treat acute angina episodes. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Animal carcinogenesis studies with sublingual nitroglycerin have not been performed. Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related fibrotic and neoplastic changes in liver, including carcinomas, andinterstitial cell tumors in testes. At high dose, the incidences of hepatocellular carcinomas in both sexes were 52% vs. 0% in controls, and incidences of testicular tumors were 52% vs. 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice. Nitroglycerin was weakly mutagenic in Ames tests performed in two different laboratories. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with doses up to about 363 mg/kg/day, p.o., or in in vitro cytogenic tests in rat and dog tissues. In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for six months prior to mating of the F0generation with treatment continuing through successive F1and F2generations. The high dose was associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect on the fertility of the F0generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males. In this three-generation study there was no clear evidence of teratogenicity. PREGNANCY: Pregnancy Category C - Animal teratology studies have not been conducted with nitroglycerin-pumpspray. Teratology studies in rats and rabbits, however, were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. There are no adequate and well-controlled studies in pregnant women. Nitroglycerin should be given to pregnant women only if clearly needed. NURSING MOTHERS: It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nitrolingual®Pumpspray is administered to a nursing woman. PEDIATRIC USE: Safety and effectiveness of nitroglycerin in pediatric patients have not been established. ADVERSE REACTIONS: Adverse reactions to oral nitroglycerin dosage forms, particularly headache and hypotension, are generally dose-related. In clinical trials at various doses of nitroglycerin, the following adverse effects have been observed: Headache, which may be severe and persistent, is the most commonly reported side effect of nitroglycerin with an incidence on the order of about 50% in some studies. Cutaneous vasodilation with flushing may occur. Transient episodes of dizziness and weakness, as well as other signs of cerebral ischemia associated with postural hypotension, may occasionally develop. Occasionally, an individual may exhibit marked sensitivity to the hypotensive effects of nitrates and severe responses (nausea, vomiting, weakness, restlessness, pallor, perspiration and collapse) may occur even with therapeutic doses. Drug rash and/or exfoliative dermatitis have been reported in patients receiving nitrate therapy. Nausea and vomiting appear to be uncommon. page 4 of 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nitrolingual®Pumpspray given to 51 chronic stable angina patients in single doses of 0.4, 0.8 and 1.6 mg as part of a double-blind, 5 period single-dose cross-over study exhibited an adverse event profile that was generally mild to moderate. Adverse events occurring at a frequency greater than 2% included: headache, dizziness, and paresthesia. Less frequently reported events in this trial included (≤2%): dyspnea, pharyngitis, rhinitis, vasodilation, peripheral edema, asthenia, and abdominal pain. OVERDOSAGE: Signs and Symptoms: Nitrate overdosage may result in: severe hypotension, persistent throbbing headache, vertigo, palpitation, visual disturbance, flushing and perspiring skin (later becoming cold and cyanotic), nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright posture), methemoglobinemia with cyanosis and anorexia, initial hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent), heart block, increased intracranial pressure with cerebral symptoms of confusion and moderate fever, paralysis and coma followed by clonic convulsions, and possibly death due to circulatory collapse. Methemoglobinemia: Case reports of clinically significant methemoglobinemia are rare at conventional doses of organic nitrates. The formation of methemoglobin is dose-related and in the case of genetic abnormalities of hemoglobin that favor methemoglobin formation, even conventional doses of organic nitrates could produce harmful concentrations of methemoglobin. Treatment of Overdosage: Keep the patient recumbent in a shock position and comfortably warm. Passive movement of the extremities may aid venous return. Administer oxygen and artificial ventilation, if necessary. If methemoglobinemia is present, administration of methylene blue (1% solution), 1-2 mg per kilogram of body weight intravenously, may be required. If an excessive quantity of Nitrolingual®Pumpspray has been recently swallowed gastric lavage may be of use. WARNING: Epinephrine is ineffective in reversing the severe hypotensive events associated with overdosage. It and related compounds are contraindicated in this situation. DOSAGE & ADMINISTRATION: At the onset of an attack, one or two metered sprays should be administered onto or under the tongue. No more than three metered sprays are recommended within a 15-minute period. If the chest pain persists, prompt medical attention is recommended. Nitrolingual®Pumpspray may be used prophylactically five to ten minutes prior to engaging in activities which might precipitate an acute attack. Each metered spray of Nitrolingual®Pumpspray delivers 48 mg of solution containing 400 mcg of nitroglycerin after an initial priming of 5 sprays. It will remain adequately primed for 6 weeks. If the product is not used within 6 weeks it can be adequately reprimed with 1 spray. Longer storage periods without use may require up to 5 repriming sprays. There are 60 or 200 metered sprays per bottle. The total number of available doses is dependent, however, on the number of sprays per use (1 or 2 sprays), and the frequency of repriming. The transparent container can be used for continuous monitoring of the consumption. The end of the pump should be covered by the fluid level. Once fluid falls below the level of the center tube, sprays will not be adequate and the container should be replaced. As with all other sprays, there is a residual volume of fluid at the bottom of the bottle which cannot be used. During application the patient should rest, ideally in the sitting position. The container should be held vertically with the valve head uppermost and the spray orifice as close to the mouth as possible. The dose should preferably be sprayed onto the tongue by pressing the button firmly and the mouth should be closed immediately after each dose. THE SPRAY SHOULD NOT BE INHALED. The medication should not be expectorated or the mouth rinsed for 5 to 10 minutes following administration. Patients should be instructed to familiarize themselves with the position of the spray orifice, which can be identified by the finger rest on top of the valve, in order to facilitate orientation for administration at night. HOW SUPPLIED: Each box of Nitrolingual® Pumpspray contains either one or two clear glass bottle(s) coated with red transparent plastic which assists in containing the glass and medication should the bottle be shattered. Each bottle contains 4.9 g or 12 g (Net Content) of nitroglycerin lingual spray which will deliver 60 or 200 metered sprays containing 400 mcg of nitroglycerin per spray after priming. page 5 of 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nitrolingual Pumpspray is available as: • 60-dose (4.9 g) single bottle NDC 59630-300-65 • 200-dose (12 g) single bottle NDC 59630-300-20 • Duo Pack (one 4.9 g and one 12 g bottle) NDC 59630-300-26 Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F) [see USP Controlled Room Temperature]. Note: Nitrolingual®Pumpspray contains 20% alcohol. Do not forcefully open or burn container after use. Do not spray toward flames. Rx Only. logo Manufactured for Sciele Pharma, Inc., Atlanta, GA 30328 by G. Pohl-Boskamp GmbH & Co. KG, 25551 Hohenlockstedt, Germany. NLPS-PI-4 Rev. 02/08 page 6 of 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:52.754491	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018705s017lbl.pdf', 'application_number': 18705, 'submission_type': 'SUPPL ', 'submission_number': 17}
11,290	_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DORAL safely and effectively. See full prescribing information for DORAL. DORAL (quazepam) Tablets for oral use C-IV Initial U.S. Approval: 1985 ----------------------------RECENT MAJOR CHANGES----------------------- Dosage and Administration (2) 4/2013 Warnings and Precautions (5) 4/2013 ----------------------------INDICATIONS AND USAGE--------------------------- DORAL, a gamma-aminobutyric ( (GABAA ) agonist, is indicated for the treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. (1) ----------------------DOSAGE AND ADMINISTRATION-----------------------  Use the lowest dose effective for the patient  Recommended initial dose is 7.5 mg (2)  Split the 15 mg tablet along the score line to achieve 7.5 mg dose (2)  The elderly and debilitated may be more sensitive to benzodiazepines (2) ---------------------DOSAGE FORMS AND STRENGTHS----------------------  15 mg functionally scored tablet, oral (3) -------------------------------CONTRAINDICATIONS------------------------------  Hypersensitivity to quazepam or other benzodiazepines (4)  Established or suspected sleep apnea, or chronic pulmonary insufficiency (4) -----------------------WARNINGS AND PRECAUTIONS------------------------  CNS depressant effects: Impaired alertness and motor coordination, including risk of daytime impairment. Caution patients against driving and other activities requiring complete mental alertness (5.1)  Benzodiazepine withdrawal syndrome: avoid abrupt discontinuation in at-risk patients (5.2)  The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. (5.3)  Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.4)  Sleep driving and other complex behaviors while not fully awake. Risk increases with dose and concomitant CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes (5.5)  Worsening of depression or suicidal thinking may occur: Prescribe the least number of tablets feasible to avoid intentional overdose (5.6) ------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (>1%): drowsiness, headache, fatigue, dizziness, dry mouth, dyspepsia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Questcor Pharmaceuticals, Inc. at 1-800-465-9217 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS-------------------------------  CNS Depressants: downward dose adjustment may be necessary due to additive effects (7) -----------------------USE IN SPECIFIC POPULATIONS------------------------  Pregnancy: Based on animal data, may cause fetal harm (8.1)  Nursing Mothers: Administration of DORAL Tablets to nursing mothers is not recommended as quazepam and its metabolites are excreted in human milk. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved Medication Guide. Revised: 04/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 CNS-Depressant Effects and Daytime Impairment 5.2 Benzodiazepine Withdrawal Syndrome 5.3 Need to Evaluate for Co-morbid Disorders 5.4 Severe Anaphylactic or Anaphylactoid Reactions 5.5 Abnormal Thinking and Behavior Changes 5.6 Worsening of Depression 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse and Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Drug Interactions 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Page 1 Reference ID: 3296465 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 DORAL® (quazepam) is indicated for the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. The effectiveness of DORAL has been established in placebo-controlled clinical studies of 5 nights duration in acute and chronic insomnia. The sustained effectiveness of DORAL has been established in chronic insomnia in a sleep lab (polysomnographic) study of 28 nights duration. Because insomnia is often transient and intermittent, the prolonged administration of DORAL Tablets is generally not necessary or recommended. Since insomnia may be a symptom of several other disorders, the possibility that the complaint may be related to a condition for which there is a more specific treatment should be considered. 2 DOSAGE AND ADMINISTRATION Use the lowest dose effective for the patient, as important adverse effects of Doral are dose related. The recommended initial dose is 7.5 mg. The 7.5 mg dose can be increased to 15 mg if necessary for efficacy. The 7.5 mg dose can be achieved by splitting the 15 mg tablet along the score line. 2.2 Special populations Elderly and debilitated patients may be more sensitive to benzodiazepines. 3 DOSAGE FORMS AND STRENGTHS Tablets, 15 mg, functionally scored, capsule-shaped, light orange, slightly white speckled tablets, impressed with the product identification number 15 on one side of the tablet, and the product name (DORAL) on the other. 4 CONTRAINDICATIONS DORAL is contraindicated in patients with known hypersensitivity to quazepam or other benzodiazepines. Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of DORAL. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Patients who develop such reactions should not be rechallenged with Doral. Contraindicated in patients with established or suspected sleep apnea, or with pulmonary insufficiency. Page 2 Reference ID: 3296465 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 CNS-depressant effects and Daytime impairment Doral is a central nervous system (CNS) depressant and can impair daytime function in some patients even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of Doral may develop, patients using Doral should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness. Additive effects occur with concomitant use of other CNS depressants (e.g., other benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of Doral and concomitant CNS depressants should be considered. The potential for adverse drug interactions continues for several days following discontinuation of Doral, until serum levels of both active parent drug and psychoactive metabolites decline. Use of Doral with other sedative-hypnotics is not recommended. Alcohol generally should not be used during treatment with Doral. The risk of next-day psychomotor impairment is increased if Doral is taken with less than a full night of sleep remaining (7- to 8 hours); if higher than the recommended dose is taken; if co-administered with other CNS depressants[see Dosage and Administration (2.3)]. 5.2 Benzodiazepine Withdrawal Syndrome A withdrawal syndrome similar to that from alcohol (e.g., convulsions, tremor, abdominal and muscle cramps, vomiting, and sweating) can occur following abrupt discontinuation of Doral. The more severe withdrawal effects are usually limited to patients taking higher than recommended doses over an extended time. Abrupt discontinuation should be avoided in such patients, and the dose gradually tapered. Prescribers should monitor patients for tolerance, abuse, and dependence. Milder withdrawal symptoms (e.g., dysphoria and insomnia) can occur following abrupt discontinuation of benzodiazepines taken at therapeutic levels for short periods [See Drug Abuse and Dependence (9)]. 5.3 Need to Evaluate for Co-morbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs. Page 3 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.4 Severe Anaphylactic and Anaphylactoid Reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including DORAL. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with DORAL should not be rechallenged with the drug. 5.5 Abnormal Thinking and Behavior Changes Abnormal thinking and behavior changes have been reported in patients treated with sedative- hypnotics including Doral. Some of these changes include decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, and depersonalization. Visual and auditory hallucinations have also been reported. Amnesia, and other neuro-psychiatric symptoms may occur. Paradoxical reactions such as stimulation, agitation, increased muscle spasticity, and sleep disturbances may occur unpredictably. Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake, with amnesia for the event) have been reported with use of sedative-hypnotics. These behaviors can occur with initial treatment or in patients previously tolerant of Doral or other sedative-hypnotics. Although these behaviors can occur with use at therapeutic doses, risk is increased by higher doses or concomitant use of alcohol or other CNS depressants. Due to risk to the patient and community, Doral should be discontinued if "sleep-driving" occurs. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. 5.6 Worsening of Depression Benzodiazepines may worsen depression. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label:  CNS-depressant effects and next-day impairment [see Warnings and Precautions (5.1)]  Benzodiazepine withdrawal syndrome[see Warnings and Precautions (5.2)]  Abnormal thinking and behavior changes, and complex behaviors[see Warnings and Precautions (5.5)]  Worsening of depression[see Warnings and Precautions (5.6)] Page 4 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The table shows adverse reactions occurring at an incidence of 1% or greater in relatively short- duration, placebo-controlled clinical trials of Doral. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in actual practice. DORAL 15 mg PLACEBO NUMBER OF PATIENTS 267 268 % OF PATIENTS REPORTING Central Nervous System Daytime Drowsiness 12 3 Headache 5 2 Fatigue 2 0 Dizziness 2 <1 Autonomic Nervous System Dry Mouth 2 <1 Gastrointestinal System Dyspepsia 1 <1 A double-blind, controlled sleep laboratory study (N=30) in elderly patients compared the effects of quazepam 7.5 mg and 15 mg to that of placebo over a period of 7 days. Both the 7.5 mg and 15 mg doses appeared to be well tolerated. Caution must be used in interpreting this data due to the small size of the study. 7 DRUG INTERACTIONS Benzodiazepines, including DORAL, produce additive CNS depressant effects when co administered with ethanol or other CNS depressants (e.g. psychotropic medications, anticonvulsants, antihistamines). Downward dose adjustment of Doral and/or concomitant CNS depressants may be necessary because of additive effects. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can Page 5 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda development dependence, and subsequently withdrawal, during the postnatal period. Although administration of quazepam to pregnant animals did not indicate a risk for adverse effects on morphological development at clinically relevant doses, data for other benzodiazepines suggest the possibility of adverse developmental effects (long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines. DORAL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Developmental toxicity studies of quazepam in mice at doses up to 400 times the human dose (15 mg) revealed no major drug-related malformations. Minor fetal skeletal variations that occurred were delayed ossification of the sternum, vertebrae, distal phalanges and supraoccipital bones, at doses approximately 70 and 400 times the human dose. A developmental toxicity study of quazepam in New Zealand rabbits at doses up to approximately 130 times the human dose demonstrated no effect on fetal morphology or development of offspring. 8.3 Nursing Mothers Quazepam and its metabolites are excreted in human milk. Caution should be exercised when administering DORAL to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Doral may cause confusion and over-sedation in the elderly. Elderly patients generally should be started on a low dose of Doral and observed closely. Elderly and debilitated patients may be more sensitive to benzodiazepines, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. A double-blind controlled sleep laboratory study (N=30) compared the effects of quazepam 7.5 mg and 15 mg to that of placebo over a period of 7 days. Both the 7.5 mg and 15 mg doses appeared to be well tolerated. Caution must be used in interpreting this data due to the small size of the study. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Quazepam is classified as a Schedule IV controlled substance by federal regulation. Page 6 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda s tructural formula 9.2 Abuse and Dependence Addiction-prone individuals (e.g. history of drug addiction or alcoholism) should be under careful surveillance when receiving Doral because of increased risk of abuse and dependence. Benzodiazepine withdrawal symptoms can occur following discontinuation of Doral [see Warnings and Precautions (5.2)]. Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects. Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. 10 OVERDOSAGE Contact a poison control center for up-to-date information on the management of benzodiazepine overdose. Manifestations of Doral overdose include somnolence, confusion, and coma. General supportive measures should be employed, along with immediate gastric lavage. Dialysis is of limited value. Flumazenil may be useful, but can contribute to the appearance of neurological symptoms including convulsions. Hypotension may be treated by appropriate medical intervention. Animal experiments suggest that forced diuresis or hemodialysis are of little value in treating Doral overdose. As with the management of intentional overdose with any drug, the possibility of multiple drug ingestion should be considered. 11 DESCRIPTION DORAL contains quazepam, a trifluoroethyl benzodiazepine hypnotic agent, having the chemical name 7-chloro-5- (o-fluoro-phenyl)-1,3-dihydro-1-(2,2,2-trifluoroethyl)-2H-1,4 benzodiazepine-2-thione and the following structural formula: Page 7 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Quazepam has the empirical formula C17H11ClF4N2S, and a molecular weight of 386.8. It is a white crystalline compound, soluble in ethanol and insoluble in water. Each DORAL Tablet contains 15 mg of quazepam. The inactive ingredients for DORAL Tablets include cellulose, corn starch, FD&C Yellow No. 6 Al Lake, lactose, magnesium stearate, silicon dioxide, and sodium lauryl sulfate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Quazepam, like other central nervous system agents of the 1,4-benzodiazepine class, presumably exerts its effects by binding to stereo-specific receptors at several sites within the central nervous system (CNS). The exact mechanism of action is unknown. 12.3 Pharmacokinetics Absorption: Quazepam is rapidly (absorption half-life of about 30 minutes) and well absorbed from the gastrointestinal tract. The peak plasma concentration of quazepam is approximately 20 ng/mL after a 15 mg dose and occurs at about 2 hours. Metabolism: Quazepam, the active parent compound, is extensively metabolized in the liver; two of the plasma metabolites are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. All three compounds show CNS depressant activity. Distribution: The degree of plasma protein binding for quazepam and its two major metabolites is greater than 95%. Elimination: Following administration of 14C-quazepam, 31% of the dose appeared in the urine and 23% in the feces over five days; only trace amounts of unchanged drug were present in the urine. The mean elimination half-life of quazepam and 2-oxoquazepam is 39 hours and that of N desalkyl-2-oxoquazepam is 73 hours. Steady-state levels of quazepam and 2-oxoquazepam are attained by the seventh daily dose and that of N-desalkyl-2-oxoquazepam by the thirteenth daily dose. Special Populations: Geriatrics: The pharmacokinetics of quazepam and 2-oxoquazepam in geriatric subjects are comparable to those seen in young adults; as with desalkyl metabolites of other benzodiazepines, the elimination half-life of N-desalkyl-2-oxoquazepam in geriatric patients is about twice that of young adults. 12.4 Drug Interactions Bupropion (a CYP2B6 substrate): Co-administration of a single dose of 150 mg Bupropion Hydrochloride XL with steady state quazepam did not significantly affect the AUC and Cmax of bupropion or its primary metabolite, hydroxybupropion. Page 8 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Quazepam showed no evidence of carcinogenicity in oral carcinogenicity studies in mice and hamsters. Mutagenesis Quazepam was negative in the bacterial reverse mutation (Ames) assay and equivocal in the mouse lymphoma tk assay. Impairment of Fertility Reproduction studies in mice conducted with quazepam at doses equal to 60 and 180 times the human dose of 15 mg produced slight reductions in fertility rate. Similar reductions in fertility rate have been reported in mice dosed with other benzodiazepines, and is believed to be related to the sedative effects of these drugs at high doses. 14 CLINICAL STUDIES The effectiveness of DORAL was established in placebo-controlled clinical studies of 5 nights duration in acute and chronic insomnia. The sustained effectiveness of DORAL was established in chronic insomnia in a sleep laboratory (polysomnographic) study of 28 nights duration. In the sleep laboratory study, DORAL significantly decreased sleep latency and total wake time, and significantly increased total sleep time and percent sleep time, for one or more nights. Doral 15 mg was effective on the first night of administration. Sleep latency, total wake time and wake time after sleep onset were still decreased and percent sleep time was still increased for several nights after the drug was discontinued. Percent slow wave sleep was decreased, and REM sleep was essentially unchanged. No transient sleep disturbance, such as “rebound insomnia,” was observed after withdrawal of the drug in sleep laboratory studies in 12 patients using 15 mg doses. In outpatient studies, DORAL Tablets improved all subjective measures of sleep including sleep latency, duration of sleep, number of awakenings, occurrence of early morning awakening, and sleep quality. Some effects were evident on the first night of administration of DORAL (sleep latency, number of awakenings, and duration of sleep). A double-blind, controlled sleep laboratory study (N=30) in elderly patients compared the effects of quazepam 7.5 mg and 15 mg to that of placebo over a period of 7 days. Both the 7.5 mg and 15 mg doses appeared to be effective. Caution must be used in interpreting this data due to the small size of the study. 16 HOW SUPPLIED DORAL Tablets, 15 mg, functionally scored, capsule-shaped, light orange, slightly white speckled tablets, impressed with the product identification number 15 on one side of the tablet, and the product name (DORAL) on the other. Page 9 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 mg Bottles of 100 NDC 63004-7734-1 Store DORAL® Tablets at controlled room temperature 20°-25°C (68°-77°F). 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Inform patients about the benefits and risks of DORAL, stressing the importance of use as directed. Assist patients in understanding the Medication Guide and instruct them to read it with each prescription refill. CNS depressant Effects and Next-Day Impairment Tell patients that Doral can cause next-day impairment, even in the absence of symptoms. Caution patients against driving or engaging in other hazardous activities or activities requiring complete mental alertness when using Doral. Tell patients that daytime impairment may persist for several days following discontinuation of Doral. Withdrawal Instruct patients to contact you before stopping or decreasing the dose of Doral, because withdrawal symptoms can occur. Abnormal thinking and behavior change Instruct patients that sedative hypnotics can cause abnormal thinking and behavior change, including “sleep-driving” and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms. Severe Allergic Reactions Inform patients that severe allergic reactions can occur from Doral. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if these occur. Suicide Tell patients that Doral can worsen depression, and to immediately report any suicidal thoughts. Alcohol and other drugs Ask patients about alcohol consumption, medicines they are taking now, and drugs they may be taking without a prescription. Advise patients that alcohol generally should not be used during treatment with Doral. Pregnancy Instruct patients to inform you if they are nursing or pregnant, or may become pregnant while taking Doral. Tolerance, Abuse, and Dependence Tell patients not to increase the dose of Doral on their own, and to inform you if they believe the drug “does not work”. Page 10 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo Manufactured for: Questcor Pharmaceuticals, Inc. Hayward, CA 94545 USA phone (800) 411-3065 (510) 400-0700 fax (510) 400-0799 Manufactured by: Meda Pharmaceuticals, Inc. Somerset, NJ 08873-4120 Under license from Baker Norton Pharmaceuticals, Inc. Printed in USA. IN-1500-06 Rev. 04/13 Page 11 Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE DORAL (DOR-al) (quazepam) Tablets (C-IV) Read the Medication Guide that comes with DORAL before you start 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 healthcare provider about your medical condition or treatment. What is the most important information I should know about DORAL? Doral may cause serious side effects that you may not know are happening to you. These side effects include: • sleepiness during the day • not thinking clearly • act strangely, confused, or upset  “sleep-walking” or doing other activities when you are asleep like: o eating o talking o having sex o driving a car Call your healthcare provider right away if you find out that you have done any of the above activities after taking DORAL. What is DORAL? DORAL is a prescription medicine used to treat certain types of insomnia including difficulty falling asleep, waking up often during the night, or waking up early in the morning. It is not known if DORAL is safe and effective in children. DORAL is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep DORAL in a safe place to prevent misuse and abuse. Selling or giving away DORAL 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. Who should not take DORAL? Do not take DORAL if you:  are allergic to quazepam or any of the ingredients in DORAL. See the end of this Medication Guide for a complete list of ingredients in DORAL. Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  have had an allergic reaction to other sleep medicines or sedatives such as benzodiazepines. Symptoms of a serious allergic reaction to quazepam can include: • swelling of your face, lips, and throat that may cause difficulty breathing or swallowing • nausea and vomiting • have sleep apnea, snoring, breathing or lung problems Talk to your healthcare provider before taking this medicine if you have any of these conditions. What should I tell my healthcare provider before taking DORAL? DORAL may not be right for you. Before taking DORAL, tell your healthcare provider about all of your health conditions, including if you:  have a history of depression, mental illness or, suicidal thoughts  have a history of drug or alcohol abuse or addiction  have lung disease or breathing problems  are pregnant or plan to become pregnant. It is not known if DORAL can harm your unborn baby.  are breastfeeding, or plan to breastfeed. DORAL can pass through your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take DORAL. Tell your healthcare provider about all of the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects. Do not take DORAL with other medicines that can make you sleepy unless your healthcare provider tells you to. Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist each time you get a new medicine. How should I take DORAL?  See “What is the most important information I should know about DORAL?”  Take DORAL exactly as your healthcare providers tell you to take it.  Do not stop taking DORAL without talking to your healthcare provider, drug withdrawal symptoms can happen.  DORAL comes in 15 mg tablets. Your healthcare provider may start your DORAL dose at 7.5 mg which is half a tablet. Talk to your healthcare provider or pharmacist about your dose schedule. Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • You should not drink alcohol while you are taking DORAL.  Call your healthcare provider if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problem.  If you take too much DORAL or overdose, get emergency treatment right away. What are the possible side effects of DORAL? DORAL may cause serious side effects, including:  getting out of bed while not being fully awake and doing an activity that you do not know you are doing. See “What is the most important information I should know about DORAL?”  abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.  memory loss  severe allergic reactions. Symptoms include swelling of the tongue or throat, and trouble breathing. Get emergency medical help right away if you have these symptoms after taking DORAL. Call your healthcare provider right away if you have any of the above side effects or any other side effects that worry you while using DORAL. Common side effects of DORAL include:  drowsiness  headache  feeling very tired  dizziness  dry mouth  upset stomach After you stop taking a sleep medicine, you may have symptoms for the next 1 to 2 days such as:  trouble sleeping  vomiting  nausea  stomach cramps  flushing  panic attack  lightheadedness  nervousness  uncontrolled crying  stomach area pain Tell your healthcare provider if you have any side effect that bothers you or that Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda does not go away. These are not all the possible side effects of DORAL. Ask your healthcare provider 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 DORAL?  Store at room temperature between 68°F to 77° F (20°C to 25°C).  Keep DORAL and all medicines out of the reach of children General information about the safe and effective use of Doral. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DORAL for a condition for which it was not prescribed. Do not share DORAL with other people, even if they have the same symptoms that you have. It may harm them and it is against the law. This Medication Guide summarizes the most important information about DORAL. If you would like more information about DORAL, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DORAL that is written for healthcare professionals. If you would like more information, go to http://www.DORALforsleep.com or call Questcor Pharmaceuticals at 1-800-411-3065DORAL. What are the ingredients in DORAL? Active Ingredient: quazepam Inactive Ingredients: cellulose, corn starch, FD&C Yellow No. 6 Al Lake, lactose, magnesium stearate, silicon dioxide, and sodium lauryl sulfate. Distributed by Questcor Pharmaceuticals, Inc. Hayward, CA 94545 USA This Medication Guide has been approved by the U.S. Food and Drug Administration. (IS-1500-02 Rev. 00/13 Month and year MG is approved) Reference ID: 3296465 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:52.838750	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018708s020s021lbl.pdf', 'application_number': 18708, 'submission_type': 'SUPPL ', 'submission_number': 21}
11,291	MYCELEX® (clotrimazole) TROCHE FOR TOPICAL ORAL ADMINISTRATION DESCRIPTION Each Mycelex® Troche contains 10 mg clotrimazole [1-(o-chloro-α,α-diphenylbenzyl) imidazole], a synthetic antifungal agent, for topical use in the mouth. Structural Formula: Chemical Formula: C22H17CIN2 The troche dosage form is a large, slowly dissolving tablet (lozenge) containing 10 mg of clotrimazole dispersed in dextrose, microcrystalline cellulose, povidone, and magnesium stearate. CLINICAL PHARMACOLOGY Clotrimazole is a broad-spectrum antifungal agent that inhibits the growth of pathogenic yeasts by altering the permeability of cell membranes. The action of clotrimazole is fungistatic at concentrations of drug up to 20 mcg/mL and may be fungicidal in vitro against Candida albicans and other species of the genus Candida at higher concentrations. No single-step or multiple-step resistance to clotrimazole has developed during successive passages of Candida albicans in the laboratory; however, individual organism tolerance has been observed during successive passages in the laboratory. Such in vitro tolerance has resolved once the organism has been removed from the antifungal environment. After oral administration of a 10 mg clotrimazole troche to healthy volunteers, concentrations sufficient to inhibit most species of Candida persist in saliva for up to three hours following the approximately 30 minutes needed for a troche to dissolve. The long term persistence of drug in saliva appears to be related to the slow release of clotrimazole from the oral mucosa to which the drug is apparently bound. Repetitive dosing at three hour intervals maintains salivary levels above the minimum inhibitory concentrations of most strains of Candida; however, the relationship between in vitro susceptibility of pathogenic fungi to clotrimazole and prophylaxis or cure of infections in humans has not been established. In another study, the mean serum concentrations were 4.98 ± 3.7 and 3.23 ± 1.4 nanograms/mL of clotrimazole at 30 and 60 minutes, respectively, after administration as a troche. INDICATIONS AND USAGE Mycelex® Troches are indicated for the local treatment of oropharyngeal candidiasis.The diagnosis should be confirmed by a KOH smear and/or culture prior to treatment. Mycelex® Troches are also indicated prophylactically to reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions that include chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation. There are no data from adequate and well-controlled trials to establish the safety and efficacy of this product for prophylactic use in patients immunocompromised by etiologies other than those listed in the previous sentence. (See DOSAGE AND ADMINISTRATION.) CONTRAINDICATIONS Mycelex® Troches are contraindicated in patients who are hypersensitive to any of its components. WARNING Mycelex® Troches are not indicated for the treatment of systemic mycoses including systemic candidiasis. PRECAUTIONS Abnormal liver function tests have been reported in patients treated with clotrimazole troches; elevated SGOT levels were reported in about 15% of patients in the clinical trials. In most cases the elevations were minimal and it was often impossible to distinguish effects of clotrimazole from those of other therapy and the underlying disease (malignancy in most cases). Periodic assessment of hepatic function is advisable particularly in patients with pre-existing hepatic impairment. Since patients must be instructed to allow each troche to dissolve slowly in the mouth in order to achieve maximum effect of the medication, they must be of such an age and physical and/or mental condition to comprehend such instructions. Carcinogenesis: An 18 month dosing study with clotrimazole in rats has not revealed any carcinogenic effect. Usage in Pregnancy: Pregnancy Category C: Clotrimazole has been shown to be embryotoxic in rats and mice when given in doses 100 times the adult human dose (in mg/kg), possibly secondary to maternal toxicity. The drug was not teratogenic in mice, rabbits, and rats when given in doses up to 200, 180, and 100 times the human dose. Clotrimazole given orally to mice from nine weeks before mating through weaning at a dose 120 times the human dose was associated with impairment of mating, decreased number of viable young, and decreased survival to weaning. No effects were observed at 60 times the human dose. When the drug was given to rats during a similar time period at 50 times the human dose, there was a slight decrease in the number of pups per litter and decreased pup viability. There are no adequate and well controlled studies in pregnant women. Clotrimazole troches should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. PEDIATRIC USE Safety and effectiveness of clotrimazole in children below the age of 3 years have not been established; therefore, its use in such patients is not recommended. The safety and efficacy of the prophylactic use of clotrimazole troches in children have not been established. GERIATRIC USE Clinical studies of clotrimazole did not include sufficient numbers of subjects aged 65 and over to determine whether they responsd differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. ADVERSE REACTIONS Abnormal liver function tests have been reported in patients treated with clotrimazole troches; elevated SGOT levels were reported in about 15% of patients in the clinical trials (See Precautions section). Nausea, vomiting, unpleasant mouth sensations and pruritus have also been reported with the use of the troche. OVERDOSAGE No data available. DRUG ABUSE AND DEPENDENCE No data available. DOSAGE AND ADMINISTRATION Mycelex® Troches are administered only as a lozenge that must be slowly dissolved in the mouth. The recommended dose is one troche five times a day for fourteen consecutive days. Only limited data are available on the safety and effectiveness of the clotrimazole troche after prolonged administration; therefore, therapy should be limited to short term use, if possible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For prophylaxis to reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions that include chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation, the recommended dose is one troche three times daily for the duration of chemotherapy or until steroids are reduced to maintenance levels. HOW SUPPLIED Mycelex® Troches, white discoid, uncoated tablets are supplied in bottles of 70 and 140. Mycelex® Troches are also available for institutional use in foil packages of 70 tablets. Each tablet will be identified with the following: Mycelex 10. Tablet Strength NDC Code Identification Bottles of 70: 10 mg NDC 17314-9400-1 MYCELEX 10 Bottles of 140: 10 mg NDC 17314-9400-3 MYCELEX 10 Unit Dose Package of 70: 10 mg NDC 17314-9400-2 MYCELEX 10 Store below 86°F (30°C). Avoid freezing. Rx Only Manufactured by Bayer Corporation West Haven, CT 06516 Distributed by ALZA Pharmaceuticals A Division of ALZA Corporation Mountain View, CA 94043 PD500187 BAY 5097 10437 ©2001 Bayer Corporation 4/01 Printed in USA TM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:53.154612	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18713slr019_mycelex_lbl.pdf', 'application_number': 18713, 'submission_type': 'SUPPL ', 'submission_number': 19}
11,292	N O N c O BILTRICIDE® TABLETS (praziquantel) DESCRIPTION BILTRICIDE® (praziquantel) is a trematodicide provided in tablet form for the oral treatment of schistosome infections and infections due to liver fluke. BILTRICIDE® (praziquantel) is 2-(cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinolin-4-one with the molecular formula; C19H24N2O2. The structural formula is as follows: Praziquantel is a white to nearly white crystalline powder of bitter taste. The compound is stable under normal conditions and melts at 136-140°C with decomposition. The active substance is hygroscopic. Praziquantel is easily soluble in chloroform and dimethylsulfoxide, soluble in ethanol and very slightly soluble in water. BILTRICIDE tablets contain 600 mg of praziquantel. Inactive ingredients: corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide and hypromellose. CLINICAL PHARMACOLOGY Praziquantel induces a rapid contraction of schistosomes by a specific effect on the permeability of the cell membrane. The drug further causes vacuolization and disintegration of the schistosome tegument. After oral administration BILTRICIDE® is rapidly absorbed (80%), subjected to a first pass effect, metabolized and eliminated by the kidneys. Maximal serum concentration is achieved 1-3 hours after dosing. The half-life of praziquantel in serum is 0.8-1.5 hours. Special Populations: The pharmacokinetics of praziquantel were studied in 40 patients with Schistosoma mansoni infections with varying degrees of hepatic dysfunction (See table1). In patients with schistosomiasis, the pharmacokinetic parameters did not differ significantly between those with normal hepatic function (Group 1) and those with mild (Child-Pugh B) hepatic impairment. However, in patients with moderate-to-severe hepatic dysfunction (Child- Pugh Class B and C), praziquantel half-life, Cmax, and AUC increased progressively with the degree of hepatic impairment. In Child-Pugh class B, the increases in mean half-life, Cmax, and AUC relative to Group 1 were 1.58-fold, 1.76-fold, and 3.55-fold, respectively. The corresponding increases in Child-Pugh class C patients were 2.82-fold, 4.29-fold, and 15-fold for half-life, Cmax, and AUC. Table 1: Pharmacokinetic parameters of praziquantel in four groups of patients with varying degrees of liver function following administration of 40 mg/kg under fasting conditions. Patient Group Half-life (hr) Tmax (hr) Cmax (µg/mL) AUC (µg/mL* hr) Normal hepatic function (Group 1) 2.99 ± 1.28 1.48 ± 0.74 0.83 ± 0.52 3.02 ± 0.59 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Child-Pugh A (Group 2) 4.66 ± 2.77 1.37 ± 0.61 0.93 ± 0.58 3.87 ± 2.44 Child-Pugh B (Group 3) 4.74 ± 2.16a 2.21 ± 0.78a,b 1.47 ± 0.74a,b 10.72 ± 5.53a,b Child-Pugh C (Group 4) 8.45 ± 2.62a,b,c 3.2 ± 1.05a,b,c 3.57 ± 1.30a,b,c 45.35 ± 17.50a,b,c a) p<0.05 compared to Group 1 b) p<0.05 compared to Group 2 c) p<0.05 compared to Group 3 INDICATIONS AND USAGE BILTRICIDE® is indicated for the treatment of infections due to: all species of schistosoma (e.g. Schistosoma mekongi, Schistosoma japonicum, Schistosoma mansoni and Schistosoma hematobium), and infections due to the liver flukes, Clonorchis sinensis/ Opisthorchis viverrini (approval of this indication was based on studies in which the two species were not differentiated). CONTRAINDICATIONS BILTRICIDE® must not be given to patients who previously have shown hypersensitivity to the drug. Since parasite destruction within the eye may cause irreparable lesions, ocular cysticercosis should not be treated with this compound. WARNINGS Therapeutically effective levels of praziquantel may not be achieved with concomitant administration of strong inducers of cytochrome P450 such as rifampin. PRECAUTIONS General: Approximately 80% of a dose of praziquantel is excreted in the kidneys, almost exclusively (>99%) in the form of metabolites. Excretion might be delayed in patients with impaired renal function, but accumulation of unchanged drug would not be expected. Therefore, dose adjustment for renal impairment is not considered necessary. Nephrotoxic effects of praziquantel or its metabolites are not known. Caution should be exercised in the administration of the usual recommended dose of praziquantel to hepatosplenic schistosomiasis patients with moderate to severe liver impairment (Child Pugh Class B and C). Reduced metabolism of praziquantel by the liver in these patients may lead to considerably higher and longer lasting plasma concentrations of unmetabolized praziquantel (See CLINICAL PHARMACOLOGY/Special Populations). Minimal increases in liver enzymes have been reported in some patients. Patients suffering from cardiac irregularities should be monitored during treatment. When schistosomiasis or fluke infection is found to be associated with cerebral cysticercosis it is advised to hospitalize the patient for the duration of treatment. Information for Patients: Patients should be warned not to drive a car and not to operate machinery on the day of BILTRICIDE® treatment and the following day. Drug Interactions: Concomitant administration of drugs that increase the activity of drug metabolizing liver enzymes (Cytochrome P450), e.g. antiepileptic drugs (phenytoin, phenobarbital and carbamazepine), dexamethasone, may reduce plasma levels of praziquantel. Concomitant administration of rifampin should be avoided (see WARNINGS). Concomitant administration of drugs that decrease the activity of drug metabolizing liver enzymes (Cytochrome P 450), e.g. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda cimetidine, ketoconazole, itraconazole, erythromycin may increase plasma levels of praziquantel. Chloroquine, when taken simultaneously, may lead to lower concentrations of praziquantel in blood. The mechanism of this drug-drug interaction is unclear. Grapefruit juice was reported to produce a 1.6-fold increase in the Cmax and a 1.9-fold increase in the AUC of praziquantel. However, the effect of this exposure increase on the therapeutic effect and safety of praziquantel has not been systematically evaluated. Mutagenesis, Carcinogenesis: Mutagenic effects in Salmonella tests found by one laboratory have not been confirmed in the same tested strain by other laboratories. Long term carcinogenicity studies in rats and golden hamsters did not reveal any carcinogenic effect. Pregnancy Category B: Reproduction studies have been performed in rats and rabbits at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to praziquantel. There are, however, no adequate and well-controlled studies in pregnant women. An increase of the abortion rate was found in rats at three times the single human therapeutic dose. While animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing mothers: Praziquantel appeared in the milk of nursing women at a concentration of about 1/4 that of maternal serum. Women should not nurse on the day of BILTRICIDE® treatment and during the subsequent 72 hours. Pediatric use: Safety in children under 4 years of age has not been established. Geriatric use: Clinical studies of praziquantel did not include a sufficient number of subjects ages 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, but greater sensitivity of some older patients cannot be ruled out. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in these patients. ADVERSE EVENTS In general BILTRICIDE® is very well tolerated. Side effects are usually mild and transient and do not require treatment. The following side effects were observed generally in order of severity: malaise, headache, dizziness, abdominal discomfort with or without nausea, rise in temperature and, rarely, urticaria. Such symptoms can, however, also result from the infection itself. Such side effects may be more frequent and/or serious in patients with a heavy worm burden. In patients with liver impairment caused by the infection, no adverse effects of BILTRICIDE® have occurred which would necessitate restriction in use. Post Marketing Adverse Event Reports: Additional adverse events reported from worldwide post marketing experience and from publications with praziquantel include: abdominal pain, allergic reaction (generalized hypersensitivity) including polyserositis, anorexia, arrhythmia (including bradycardia, ectopic rhythms, ventricular fibrillation, AV blocks), asthenia, bloody diarrhea, convulsion, myalgia, somnolence, vertigo, vomiting OVERDOSAGE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In rats and mice the acute LD50 was about 2,500 mg/kg. No data are available in humans. In the event of overdose a fast-acting laxative should be given. DOSAGE AND ADMINISTRATION The dosage recommended for the treatment of schistosomiasis is: 20 mg/kg bodyweight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The recommended dose for clonorchiasis and opisthorchiasis is: 25 mg/kg bodyweight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The tablets should be washed down unchewed with water during meals. Keeping the tablets or segments thereof in the mouth can reveal a bitter taste which can promote gagging or vomiting. HOW SUPPLIED BILTRICIDE® is supplied as a 600 mg white to orange tinged, film-coated, oblong tablet with three scores. The tablet is coded with “BAYER” on one side and “LG” on the reverse side. When broken each of the four segments contain 150 mg of active ingredient so that the dosage can be easily adjusted to the patient’s bodyweight. Segments are broken off by pressing the score (notch) with thumbnails. If 1/4 of a tablet is required, this is best achieved by breaking the segment from the outer end. BILTRICIDE® is available in bottles of 6 tablets. Strength NDC Bottles of 6: 600 mg 0026-2521-06 Store below 86°F (30°C). Bayer Pharmaceuticals Corporation 400 Morgan Lane West Haven, CT 06516 USA Made in Germany Rx Only EMBAY 8440 Bayer Pharmaceuticals Corporation Printed in U.S.A. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:53.235370	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18714s008,009lbl.pdf', 'application_number': 18714, 'submission_type': 'SUPPL ', 'submission_number': 8}
11,293	BILTRICIDE® TABLETS (praziquantel) DESCRIPTION BILTRICIDE® (praziquantel) is a trematodicide provided in tablet form for the oral treatment of schistosome infections and infections due to liver fluke. BILTRICIDE (praziquantel) is 2-(cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinolin-4-one with the molecular formula; C19H24N2O2. The structural formula is as follows: Structural formula of Biltricide (praziquantel) Praziquantel is a white to nearly white crystalline powder of bitter taste. The compound is stable under normal conditions and melts at 136-140°C with decomposition. The active substance is hygroscopic. Praziquantel is easily soluble in chloroform and dimethylsulfoxide, soluble in ethanol and very slightly soluble in water. BILTRICIDE tablets contain 600 mg of praziquantel. Inactive ingredients: corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide and hypromellose. CLINICAL PHARMACOLOGY Praziquantel induces a rapid contraction of schistosomes by a specific effect on the permeability of the cell membrane. The drug further causes vacuolization and disintegration of the schistosome tegument. After oral administration BILTRICIDE is rapidly absorbed (80%), subjected to a first pass effect, metabolized and eliminated by the kidneys. Maximal serum concentration is achieved 1-3 hours after dosing. The half-life of praziquantel in serum is 0.8-1.5 hours. Special Populations The pharmacokinetics of praziquantel were studied in 40 patients with Schistosoma mansoni infections with varying degrees of hepatic dysfunction (See table1). In patients with schistosomiasis, the pharmacokinetic parameters did not differ significantly between those with normal hepatic function (Group 1) and those with mild (Child-Pugh class A) hepatic impairment. However, in patients with moderate-to-severe hepatic dysfunction (Child-Pugh class B and C), praziquantel half-life, Cmax, and AUC increased progressively with the degree of hepatic impairment. In Child-Pugh class B, the increases in mean half-life, Cmax, and AUC relative to Group 1 were 1.58-fold, 1.76-fold, and 3.55-fold, respectively. The corresponding increases in Child-Pugh class C patients were 2.82-fold, 4.29-fold, and 15-fold for half-life, Cmax, and AUC. Table 1: Pharmacokinetic parameters of praziquantel in four groups of patients with varying degrees of liver function following administration of 40 mg/kg under fasting conditions. Pharmaco kineti c paramete rs of praz iquan tel i n four g roup s of patients with varying degrees of liver function following administration of 40 mg/kg under fasting conditions This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Normal hepatic function (Group 1) 2.99 ± 1.28 1.48 ± 0.74 0.83 ± 0.52 3.02 ± 0.59 Child-Pugh A (Group 2) 4.66 ± 2.77 1.37 ± 0.61 0.93 ± 0.58 3.87 ± 2.44 Child-Pugh B (Group 3) 4.74 ± 2.16a 2.21 ± 0.78a,b 1.47 ± 0.74a,b 10.72 ± 5.53a,b Child-Pugh C (Group 4) 8.45 ± 2.62a,b,c 3.2 ± 1.05a,b,c 3.57 ± 1.30a,b,c 45.35 ± 17.50a,b,c a) p<0.05 compared to Group 1 b) p<0.05 compared to Group 2 c) p<0.05 compared to Group 3 INDICATIONS AND USAGE BILTRICIDE is indicated for the treatment of infections due to: all species of schistosoma (for example, Schistosoma mekongi, Schistosoma japonicum, Schistosoma mansoni and Schistosoma hematobium), and infections due to the liver flukes, Clonorchis sinensis/Opisthorchis viverrini (approval of this indication was based on studies in which the two species were not differentiated). CONTRAINDICATIONS BILTRICIDE is contraindicated in patients who previously have shown hypersensitivity to the drug or any of the excipients. Since parasite destruction within the eye may cause irreversible lesions, ocular cysticercosis must not be treated with this compound. Concomitant administration with strong Cytochrome P450 (P450) inducers, such as rifampin, is contraindicated since therapeutically effective blood levels of praziquantel may not be achieved (see PRECAUTIONS/Drug Interactions). In patients receiving rifampin who need immediate treatment for schistosomiasis, alternative agents for schistosomiasis should be considered. However, if treatment with praziquantel is necessary, rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment (see PRECAUTIONS/Drug Interactions). WARNINGS Therapeutically effective levels of BILTRICIDE may not be achieved when administered concomitantly with strong P450 inducers, such as rifampin (see CONTRAINDICATIONS). PRECAUTIONS General Approximately 80% of a dose of praziquantel is excreted in the kidneys, almost exclusively (>99%) in the form of metabolites. Excretion might be delayed in patients with impaired renal function, but accumulation of unchanged drug would not be expected. Therefore, dose adjustment for renal impairment is not considered necessary. Nephrotoxic effects of praziquantel or its metabolites are not known. Caution should be exercised in the administration of the usual recommended dose of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda praziquantel to hepatosplenic schistosomiasis patients with moderate to severe liver impairment (Child-Pugh class B and C). Reduced metabolism of praziquantel by the liver in these patients may lead to considerably higher and longer lasting plasma concentrations of unmetabolized praziquantel (See CLINICAL PHARMACOLOGY/Special Populations). Minimal increases in liver enzymes have been reported in some patients. Patients suffering from cardiac irregularities should be monitored during treatment. As BILTRICIDE can exacerbate central nervous system pathology due to schistosomiasis, as a general rule this drug should not be administered to individuals reporting a history of epilepsy and/or other signs of potential central nervous systems involvement such as subcutaneous nodules suggestive of cysticercosis. When schistosomiasis or fluke infection is found to be associated with cerebral cysticercosis it is advised to hospitalize the patient for the duration of treatment. Information for Patients Patients should be warned not to drive a car and not to operate machinery on the day of BILTRICIDE treatment and the following day. Drug Interactions Concomitant administration of rifampin, a strong P450 inducer, with praziquantel is contraindicated and must be avoided (see CONTRAINDICATIONS). In a crossover study with a 2-week washout period, 10 healthy subjects ingested a single 40 mg/kg dose of praziquantel following pre-treatment with oral rifampin (600 mg daily for 5 days). Plasma praziquantel concentrations were undetectable in 7 out of 10 subjects. When a single 40 mg/kg dose of praziquantel was administered to these healthy subjects two weeks after discontinuation of rifampin, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel was given alone. In patients receiving rifampin, for example, as part of a combination regimen for the treatment of tuberculosis, alternative agents for schistosomiasis should be considered. However, if treatment with praziquantel is necessary, treatment with rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment. Concomitant administration of other drugs that increase the activity of drug metabolizing liver enzymes (P450 inducers), for example, antiepileptic drugs (phenytoin, phenobarbital and carbamazepine), and dexamethasone, may also reduce plasma levels of praziquantel. Concomitant administration of drugs that decrease the activity of drug metabolizing liver enzymes (P 450 inhibitors), for example, cimetidine, ketoconazole, itraconazole, erythromycin may increase plasma levels of praziquantel. Chloroquine, when taken simultaneously, may lead to lower concentrations of praziquantel in blood. The mechanism of this drug-drug interaction is unclear. Grapefruit juice was reported to produce a 1.6-fold increase in the Cmax and a 1.9-fold increase in the AUC of praziquantel. However, the effect of this exposure increase on the therapeutic effect and safety of praziquantel has not been systematically evaluated. Mutagenesis, Carcinogenesis Mutagenic effects in Salmonella tests found by one laboratory have not been confirmed in the same tested strain by other laboratories. Long term carcinogenicity studies in rats and golden hamsters did not reveal any carcinogenic effect. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to praziquantel. There are, however, no adequate and well-controlled studies in pregnant women. An increase of the abortion rate was found in rats at three times the single human therapeutic dose. While animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing mothers Praziquantel appeared in the milk of nursing women at a concentration of about 1/4 that of maternal serum although it is not known whether a pharmacological effect is likely to occur in children. Women should not nurse on the day of BILTRICIDE treatment and during the subsequent 72 hours. Pediatric use Safety in children under 4 years of age has not been established. Geriatric use Clinical studies of praziquantel did not include a sufficient number of subjects ages 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, but greater sensitivity of some older patients cannot be ruled out. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in these patients. ADVERSE EVENTS In general BILTRICIDE is very well tolerated. Side effects are usually mild and transient and do not require treatment. The following side effects were observed generally in order of severity: malaise, headache, dizziness, abdominal discomfort with or without nausea, rise in temperature and, rarely, urticaria. Such symptoms can, however, also result from the infection itself. Such side effects may be more frequent and/or serious in patients with a heavy worm burden. Post Marketing Adverse Event Reports Additional adverse events reported from worldwide post marketing experience and from publications with praziquantel include: abdominal pain, allergic reaction (generalized hypersensitivity) including polyserositis, anorexia, arrhythmia (including bradycardia, ectopic rhythms, ventricular fibrillation, AV blocks), asthenia, bloody diarrhea, convulsion, eosinophilia, myalgia, pruritis, somnolence, vertigo and vomiting. OVERDOSAGE In rats and mice the acute LD50 was about 2,500 mg/kg. No data are available in humans. In the event of overdose a fast-acting laxative should be given. DOSAGE AND ADMINISTRATION The dosage recommended for the treatment of schistosomiasis is: 20 mg/kg bodyweight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The recommended dose for clonorchiasis and opisthorchiasis is: 25 mg/kg bodyweight This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The tablets should be washed down unchewed with water during meals. Keeping the tablets or segments thereof in the mouth can reveal a bitter taste which can promote gagging or vomiting. HOW SUPPLIED BILTRICIDE is supplied as a 600 mg white to orange tinged, film-coated, oblong tablet with three scores. The tablet is coded with “BAYER” on one side and “LG” on the reverse side. When broken, each of the four segments contains 150 mg of active ingredient so that the dosage can be easily adjusted to the patient’s bodyweight. Segments are broken off by pressing the score (notch) with thumbnails. If 1/4 of a tablet is required, this is best achieved by breaking the segment from the outer end. BILTRICIDE is available in bottles of 6 tablets. Bottles of 6 Strength 600 mg NDC 0085-1747-01 Store below 86°F (30°C). Bayer HealthCare Pharmaceuticals Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Made in Germany Distributed and Marketed by: Schering Corporation, a subsidiary of Merck & Co., Inc. Whitehouse Station, NJ 08889, USA BILTRICIDE is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering Corporation. Rx Only 08/10 EMBAY 8440 ©2010 Bayer HealthCare Pharmaceuticals Inc. Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:53.262143	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018714s012lbl.pdf', 'application_number': 18714, 'submission_type': 'SUPPL ', 'submission_number': 12}
11,294	BILTRICIDE® TABLETS (praziquantel) MM/14 DESCRIPTION BILTRICIDE® (praziquantel) is a trematodicide provided in tablet form for the oral treatment of schistosome infections and infections due to liver fluke. BILTRICIDE (praziquantel) is 2-(cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinolin-4-one with the molecular formula; C19H24N2O2. The structural formula is as follows: structural formula Praziquantel is a white to nearly white crystalline powder of bitter taste. The compound is stable under normal conditions and melts at 136-140°C with decomposition. The active substance is hygroscopic. Praziquantel is easily soluble in chloroform and dimethylsulfoxide, soluble in ethanol and very slightly soluble in water. BILTRICIDE tablets contain 600 mg of praziquantel. Inactive ingredients: corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide and hypromellose. CLINICAL PHARMACOLOGY Praziquantel induces a rapid contraction of schistosomes by a specific effect on the permeability of the cell membrane. The drug further causes vacuolization and disintegration of the schistosome tegument. After oral administration BILTRICIDE is rapidly absorbed (80%), subjected to a first pass effect, metabolized and eliminated by the kidneys. Maximal serum concentration is achieved 1-3 hours after dosing. The half-life of praziquantel in serum is 0.8-1.5 hours. Special Populations The pharmacokinetics of praziquantel were studied in 40 patients with Schistosoma mansoni infections with varying degrees of hepatic dysfunction (See table1). In patients with schistosomiasis, the pharmacokinetic parameters did not differ significantly between those with normal hepatic function (Group 1) and those with mild (Child-Pugh class A) hepatic impairment. However, in patients with moderate-to-severe hepatic dysfunction (Child-Pugh class B and C), praziquantel half-life, Cmax, and AUC increased progressively with the degree of hepatic impairment. In Child-Pugh class B, the increases in mean half-life, Cmax, and AUC relative to Group 1 were 1.58-fold, 1.76-fold, and 3.55-fold, respectively. The corresponding increases in Child-Pugh class C patients were 2.82-fold, 4.29-fold, and 15-fold for half-life, Cmax, and AUC. Table 1: Pharmacokinetic parameters of praziquantel in four groups of patients with varying Reference ID: 3458330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda degrees of liver function following administration of 40 mg/kg under fasting conditions. Patient Group Half-life (hr) Tmax (hr) Cmax (µg/mL) AUC (µg/mL* hr) Normal hepatic function (Group 1) 2.99 ± 1.28 1.48 ± 0.74 0.83 ± 0.52 3.02 ± 0.59 Child-Pugh A (Group 2) 4.66 ± 2.77 1.37 ± 0.61 0.93 ± 0.58 3.87 ± 2.44 Child-Pugh B (Group 3) 4.74 ± 2.16a 2.21 ± 0.78a,b 1.47 ± 0.74a,b 10.72 ± 5.53a,b Child-Pugh C (Group 4) 8.45 ± 2.62a,b,c 3.2 ± 1.05a,b,c 3.57 ± 1.30a,b,c 45.35 ± 17.50a,b,c a) p<0.05 compared to Group 1 b) p<0.05 compared to Group 2 c) p<0.05 compared to Group 3 INDICATIONS AND USAGE BILTRICIDE is indicated for the treatment of infections due to: all species of schistosoma (for example, Schistosoma mekongi, Schistosoma japonicum, Schistosoma mansoni and Schistosoma hematobium), and infections due to the liver flukes, Clonorchis sinensis/Opisthorchis viverrini (approval of this indication was based on studies in which the two species were not differentiated). CONTRAINDICATIONS BILTRICIDE is contraindicated in patients who previously have shown hypersensitivity to the drug or any of the excipients. Since parasite destruction within the eye may cause irreversible lesions, ocular cysticercosis must not be treated with this compound. Concomitant administration with strong Cytochrome P450 (P450) inducers, such as rifampin, is contraindicated since therapeutically effective blood levels of praziquantel may not be achieved (see PRECAUTIONS/Drug Interactions). In patients receiving rifampin who need immediate treatment for schistosomiasis, alternative agents for schistosomiasis should be considered. However, if treatment with praziquantel is necessary, rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment (see PRECAUTIONS/Drug Interactions). WARNINGS Therapeutically effective levels of BILTRICIDE may not be achieved when administered concomitantly with strong P450 inducers, such as rifampin (see CONTRAINDICATIONS). Reference ID: 3458330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Approximately 80% of a dose of praziquantel is excreted in the kidneys, almost exclusively (>99%) in the form of metabolites. Excretion might be delayed in patients with impaired renal function, but accumulation of unchanged drug would not be expected. Therefore, dose adjustment for renal impairment is not considered necessary. Nephrotoxic effects of praziquantel or its metabolites are not known. Caution should be exercised in the administration of the usual recommended dose of praziquantel to hepatosplenic schistosomiasis patients with moderate to severe liver impairment (Child-Pugh class B and C). Reduced metabolism of praziquantel by the liver in these patients may lead to considerably higher and longer lasting plasma concentrations of unmetabolized praziquantel (See CLINICAL PHARMACOLOGY/Special Populations). Minimal increases in liver enzymes have been reported in some patients. Patients suffering from cardiac irregularities should be monitored during treatment. As BILTRICIDE can exacerbate central nervous system pathology due to schistosomiasis, as a general rule this drug should not be administered to individuals reporting a history of epilepsy and/or other signs of potential central nervous systems involvement such as subcutaneous nodules suggestive of cysticercosis. When schistosomiasis or fluke infection is found to be associated with cerebral cysticercosis it is advised to hospitalize the patient for the duration of treatment. Published in vitro data have shown a potential lack of efficacy of praziquantel against migrating schistosomulae. Data from two observational cohort studies in patients indicate that treatment with praziquantel in the acute phase of infection may not prevent progression from asymptomatic infection to acute schistosomiasis or from asymptomatic infection/ acute schistosomiasis into chronic phase. In addition, the use of praziquantel in patients with schistosomiasis may be associated with clinical deterioration (paradoxical reactions, serum sickness Jarisch-Herxheimer like reactions: sudden inflammatory immune response suspected to be caused by the release of schistosomal antigens). These reactions predominantly occur in patients treated during the acute phase of schistosomiasis. They may lead to potentially life-threatening events, for example, respiratory failure, encephalopathy, and/or cerebral vasculitis. Information for Patients Patients should be warned not to drive a car and not to operate machinery on the day of BILTRICIDE treatment and the following day. Drug Interactions Concomitant administration of rifampin, a strong P450 inducer, with praziquantel is contraindicated and must be avoided (see CONTRAINDICATIONS). In a crossover study with a 2-week washout period, 10 healthy subjects ingested a single 40 mg/kg dose of praziquantel following pre-treatment with oral rifampin (600 mg daily for 5 days). Plasma praziquantel concentrations were undetectable in 7 out of 10 subjects. When a single 40 mg/kg dose of praziquantel was administered to these healthy subjects two weeks after discontinuation of rifampin, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel was given alone. In patients receiving rifampin, for Reference ID: 3458330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda example, as part of a combination regimen for the treatment of tuberculosis, alternative agents for schistosomiasis should be considered. However, if treatment with praziquantel is necessary, treatment with rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment. Concomitant administration of other drugs that increase the activity of drug metabolizing liver enzymes (P450 inducers), for example, antiepileptic drugs (phenytoin, phenobarbital and carbamazepine), and dexamethasone, may also reduce plasma levels of praziquantel. Concomitant administration of drugs that decrease the activity of drug metabolizing liver enzymes (P 450 inhibitors), for example, cimetidine, ketoconazole, itraconazole, erythromycin may increase plasma levels of praziquantel. Grapefruit juice was reported to produce a 1.6-fold increase in the Cmax and a 1.9-fold increase in the AUC of praziquantel. However, the effect of this exposure increase on the therapeutic effect and safety of praziquantel has not been systematically evaluated. Mutagenesis, Carcinogenesis, Impairment of Fertility Mutagenicity studies of praziquantel published in the scientific literature are inconclusive. Long term oral carcinogenicity studies in rats and golden hamsters did not reveal any carcinogenic effect at doses up to 250 mg/kg/day (about half of the human daily dose based on body surface area). Praziquantel had no effect on fertility and general reproductive performance of male and female rats when given at oral doses ranging from 30 to 300 mg/kg body weight (up to 0.65 times the human daily dose based on body surface area). Pregnancy Category B Developmental toxicity studies have been performed in rats and rabbits at dose levels of 30 to 300 mg/kg body weight given repeatedly during the period of organogenesis. No harm to the fetus due to praziquantel was observed. These doses were up to 0.65 times (rats) or 1.3 times (rabbits) the highest recommended human daily dose of 75 mg/kg/day, based on body surface area. There are, however, no adequate and well-controlled studies in pregnant women. While animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing mothers Praziquantel appeared in the milk of nursing women at a concentration of about 1/4 that of maternal serum although it is not known, whether a pharmacological effect is likely to occur in children. Women should not nurse on the day of BILTRICIDE treatment and during the subsequent 72 hours. Pediatric use Safety in children under 4 years of age has not been established. Geriatric use Clinical studies of praziquantel did not include a sufficient number of subjects ages 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, but greater sensitivity of some older patients cannot be ruled out. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater Reference ID: 3458330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda in these patients. ADVERSE EVENTS The following side effects were observed generally in order of severity: malaise, headache, dizziness, abdominal discomfort with or without nausea, rise in temperature and urticaria. Such side effects may be more frequent and/or serious in patients with a heavy worm burden. Post Marketing Adverse Event Reports Additional adverse events reported from worldwide post marketing experience and from publications with praziquantel include: abdominal pain, allergic reaction (generalized hypersensitivity, including polyserositis), anorexia, arrhythmia (including bradycardia, ectopic rhythms, ventricular fibrillation, AV blocks), asthenia, bloody diarrhea, convulsion, eosinophilia, fatigue, myalgia, pruritus, rash, somnolence, vertigo and vomiting. OVERDOSAGE No data are available in humans. DOSAGE AND ADMINISTRATION The dosage recommended for the treatment of schistosomiasis is: 20 mg/kg bodyweight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The recommended dose for clonorchiasis and opisthorchiasis is: 25 mg/kg bodyweight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The tablets should be washed down unchewed with water during meals. Keeping the tablets or segments thereof in the mouth can reveal a bitter taste which can promote gagging or vomiting. HOW SUPPLIED BILTRICIDE is supplied as a 600 mg white to orange tinged, film-coated, oblong tablet with three scores. The tablet is coded with “BAYER” on one side and “LG” on the reverse side. When broken, each of the four segments contains 150 mg of active ingredient so that the dosage can be easily adjusted to the patient’s bodyweight. Segments are broken off by pressing the score (notch) with thumbnails. If 1/4 of a tablet is required, this is best achieved by breaking the segment from the outer end. BILTRICIDE is available in bottles of 6 tablets. Bottles of 6 Strength 600 mg NDC 50419-747-01 Store below 86°F (30°C). Reference ID: 3458330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Manufactured for: company logo Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Germany BILTRICIDE is a registered trademark of Bayer Aktiengesellschaft. Rx Only MM/14 ©2014 Bayer HealthCare Pharmaceuticals Inc. Printed in USA Reference ID: 3458330 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:53.318736	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018714s013lbl.pdf', 'application_number': 18714, 'submission_type': 'SUPPL ', 'submission_number': 13}
11,295	NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 1 of 57 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) Tablets for Oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years are at a considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and perform liver function tests prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects and other major malformations (5.2, 5.3) • Pancreatitis, including fatal hemorrhagic cases (5.4) -------RECENT MAJOR CHANGES------- Warnings and Precautions, Use in Women of Childbearing Potential (5.2) 10/2011 Warnings and Precautions, Birth Defects (5.3) 10/2011 -------INDICATIONS AND USAGE------- Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) -------DOSAGE AND ADMINISTRATION------- • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed. (2.1, 2.2) • Mania: Initial dose is 750 mg daily increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed. (2.3) -------DOSAGE FORMS AND STRENGTHS------- Tablets: 125 mg, 250mg and 500mg (3) -------CONTRAINDICATIONS------- • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known hypersensitivity to the drug (4, 5.11) • Urea cycle disorders (4, 5.5) -------WARNINGS AND PRECAUTIONS------- • Hepatotoxicity; monitor liver function tests (5.1) • Women of Childbearing Potential; weigh Depakote benefits of use during pregnancy against risk to the fetus (5.2) • Birth Defects; Depakote can cause fetal harm when taken during pregnancy (5.3) • Pancreatitis; Depakote should ordinarily be discontinued (5.4) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.6) • Thrombocytopenia; monitor platelet counts and coagulation tests (5.7) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.5, 5.8, 5.9) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.10) • Multi-organ hypersensitivity reaction; discontinue Depakote (5.11) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.13) -------ADVERSE REACTIONS------- • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, ambylopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss, (6.1, 6.2, 6.3). To report SUSPECTED ADVERSE REACTIONS, contact Abbott Laboratories at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------DRUG INTERACTIONS------- • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3) -------USE IN SPECIFIC POPULATIONS------- • Pregnancy: Depakote can cause congenital malformations including neural tube defects. Pregnancy registry available (5.2, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.13, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 10/2011 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 2 of 57 FULL PRESCRIBING INFORMATION: CONTENTS* BOXED WARNING 1 INDICATIONS AND USAGE 1.1 Mania 1.2 Epilepsy 1.3 Migraine 2 DOSAGE AND ADMINISTRATION 2.1 Mania 2.2 Epilepsy 2.3 Migraine 2.4 General Dosing Advice 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Use in Women of Childbearing Potential 5.3 Birth Defects and Neurobehavioral Adverse Effects 5.4 Pancreatitis 5.5 Urea Cycle Disorders 5.6 Suicidal Behavior and Ideation 5.7 Thrombocytopenia 5.8 Hyperammonemia 5.9 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use 5.10 Hypothermia 5.11 Multi-Organ Hypersensitivity Reactions 5.12 Interaction with Carbapenem Antibiotics 5.13 Somnolence in the Elderly 5.14 Monitoring: Drug Plasma Concentration 5.15 Effect on Ketone and Thyroid Function Tests 5.16 Effect on HIV and CMV Viruses Replication 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Other Patient Populations 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 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 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hepatotoxicity 17.2 Pancreatitis 17.3 Birth Defects and Neurobehavioral Development Adverse Effects 17.4 Suicidal Thinking and Behavior 17.5 Hyperammonemia 17.6 CNS depression 17.7 Multi-organ Hypersensitivity Reaction FDA-APPROVED MEDICATION GUIDE * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 3 of 57 FULL PRESCRIBING INFORMATION BOXED WARNING WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 4 of 57 warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. Because it may be a hazard to the fetus, Depakote should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment [see Warnings and Precautions (5.2) and Patient Counseling Information (17.3)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 5 of 57 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 6 of 57 Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 7 of 57 Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.13)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 8 of 57 Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose- related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.11)]. Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non- specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 9 of 57 these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Use in Women of Childbearing Potential Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, Depakote should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. 5.3 Birth Defects and Neurobehavioral Adverse Effects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 10 of 57 congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94 - 104]). The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development. In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and demonstrated behavioral deficits [see Use in Specific Populations (8.1)]. 5.4 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.5 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 11 of 57 deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.9)]. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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 Drug Patients Relative Risk: Incidence of Events in Risk Difference: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 12 of 57 with Events Per 1,000 Patients with Events Per 1,000 Patients Drug Patients/Incidence in Placebo Patients 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 Depakote 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. 5.7 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose- related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 13 of 57 5.8 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.10)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.10)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.5, 5.8)]. 5.10 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 14 of 57 5.11 Multi-organ Hypersensitivity Reaction Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.12 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.13 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 15 of 57 5.14 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.15 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.16 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 16 of 57 only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 17 of 57 Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo- treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 18 of 57 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 19 of 57 Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 20 of 57 Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 21 of 57 Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Other Patient Populations Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. Gastrointestinal The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients. CNS Effects Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)]. Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy. Dermatologic Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens- Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 22 of 57 epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7.2)]. Psychiatric Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal Weakness. Hematologic Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Hepatic Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose- related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions (5.1)]. Endocrine Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.15)]. There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established. Pancreatic Acute pancreatitis including fatalities [see Warnings and Precautions (5.4)]. Metabolic Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 23 of 57 Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia. Genitourinary Enuresis and urinary tract infection. Special Senses Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported. Other Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia. There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 24 of 57 The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β- oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.12)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 25 of 57 Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 26 of 57 Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co- administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 27 of 57 There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co- administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 28 of 57 Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D: [see Warnings and Precautions (5.3)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 29 of 57 All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. In animal studies, offspring had structural malformations similar to those seen in humans and demonstrated behavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • To prevent major seizures, women with epilepsy should not discontinue Depakote abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 30 of 57 • Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. • Patients taking valproate may develop hepatic failure [see Boxed Warning, Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% - 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other anti- epileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin, 99 [95% C.I. 94-104)]. The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 31 of 57 neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning, Warning and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 32 of 57 The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Nonclinical Developmental Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 33 of 57 A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 34 of 57 Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 35 of 57 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 36 of 57 influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 37 of 57 eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half- life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 38 of 57 The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility Carcinogenesis Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 39 of 57 incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 40 of 57 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 41 of 57 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. * p < 0.05 PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 42 of 57 In one multi-clinic, placebo-controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 43 of 57 Figure 2 The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post-randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 44 of 57 High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 45 of 57 Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 46 of 57 Figure 4. Mean 4-week Migraine Rates 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 47 of 57 Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Abbo-Pac® unit dose packages of 100……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide. 17.1 Hepatotoxicity Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. 17.2 Pancreatitis Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.4)]. 17.3 Birth Defects and Neurobehavioral Development Adverse Effects Prescribers should inform pregnant women and women of childbearing potential that use of Depakote during pregnancy increases the risk of birth defects and adverse effects on neurobehavioral development. Prescribers should advise women to use effective contraception while using valproate. When appropriate, prescribers should counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g. migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 48 of 57 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 Use in Specific Populations (8.1)]. 17.4 Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including Depakote, 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 the healthcare providers [see Warnings and Precautions (5.6)]. 17.5 Hyperammonemia Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8, 5.9)]. 17.6 CNS depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. 17.7 Multi-organ Hypersensitivity Reaction Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.11)]. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 49 of 57 Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Sprinkle Capsules DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking a Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: o nausea or vomiting that does not go away o loss of appetite o pain on the right side of your stomach (abdomen) o dark urine o swelling of your face o yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 50 of 57 2. Depakote or Depakene may harm your unborn baby. o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with Depakote or Depakene affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. o Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. o There may be other medicines to treat your condition that have a lower chance of birth defects. o All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception) unless you are planning to become pregnant. o Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: o severe stomach pain that you may also feel in your back o nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 51 of 57 Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. o 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 52 of 57 • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem call a urea cycle disorder What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non- prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Taking Depakote or Depakene 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. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 53 of 57 Know the medicines you take. Keep a list of them and show it your healthcare provider and pharmacist each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakote without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can not swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene may cause other serious side effects including: • Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 54 of 57 • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 950F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 55 of 57 These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C) • Store Depakote Delayed Release Tablets below 86°F (30°C) • Store Depakote Sprinkle Capsules between below 77°F (25°C) • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C) • Store Depakene Oral Solution below 86°F (30°C) Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene 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 Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbott.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote: Active ingredient: divalproex sodium Inactive ingredients: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 56 of 57 • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 500 mg is Mfd. by Abbott Laboratories, North Chicago, IL 60064 U.S.A. or Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 For Abbott Laboratories, North Chicago, IL 60064 U.S.A. Depakote Tablets: Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 57 of 57 For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Oral solution: Mfd. by Abbott Laboratories, North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Issued 10/2011 Abbott Laboratories This Medication Guide has been approved by the U.S. Food and Drug Administration. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:53.522047	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018723s037lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 37}
11,296	NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 1 of 57 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) Tablets for Oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years are at a considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and perform liver function tests prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects and other major malformations (5.2, 5.3) • Pancreatitis, including fatal hemorrhagic cases (5.4) -------RECENT MAJOR CHANGES------- Warnings and Precautions, Use in Women of Childbearing Potential (5.2) 10/2011 Warnings and Precautions, Birth Defects (5.3) 10/2011 -------INDICATIONS AND USAGE------- Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) -------DOSAGE AND ADMINISTRATION------- • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed. (2.1, 2.2) • Mania: Initial dose is 750 mg daily increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed. (2.3) -------DOSAGE FORMS AND STRENGTHS------- Tablets: 125 mg, 250mg and 500mg (3) -------CONTRAINDICATIONS------- • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known hypersensitivity to the drug (4, 5.11) • Urea cycle disorders (4, 5.5) -------WARNINGS AND PRECAUTIONS------- • Hepatotoxicity; monitor liver function tests (5.1) • Women of Childbearing Potential; weigh Depakote benefits of use during pregnancy against risk to the fetus (5.2) • Birth Defects; Depakote can cause fetal harm when taken during pregnancy (5.3) • Pancreatitis; Depakote should ordinarily be discontinued (5.4) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.6) • Thrombocytopenia; monitor platelet counts and coagulation tests (5.7) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.5, 5.8, 5.9) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.10) • Multi-organ hypersensitivity reaction; discontinue Depakote (5.11) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.13) -------ADVERSE REACTIONS------- • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, ambylopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss, (6.1, 6.2, 6.3). To report SUSPECTED ADVERSE REACTIONS, contact Abbott Laboratories at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------DRUG INTERACTIONS------- • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3) -------USE IN SPECIFIC POPULATIONS------- • Pregnancy: Depakote can cause congenital malformations including neural tube defects. Pregnancy registry available (5.2, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.13, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 10/2011 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 2 of 57 FULL PRESCRIBING INFORMATION: CONTENTS* BOXED WARNING 1 INDICATIONS AND USAGE 1.1 Mania 1.2 Epilepsy 1.3 Migraine 2 DOSAGE AND ADMINISTRATION 2.1 Mania 2.2 Epilepsy 2.3 Migraine 2.4 General Dosing Advice 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Use in Women of Childbearing Potential 5.3 Birth Defects and Neurobehavioral Adverse Effects 5.4 Pancreatitis 5.5 Urea Cycle Disorders 5.6 Suicidal Behavior and Ideation 5.7 Thrombocytopenia 5.8 Hyperammonemia 5.9 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use 5.10 Hypothermia 5.11 Multi-Organ Hypersensitivity Reactions 5.12 Interaction with Carbapenem Antibiotics 5.13 Somnolence in the Elderly 5.14 Monitoring: Drug Plasma Concentration 5.15 Effect on Ketone and Thyroid Function Tests 5.16 Effect on HIV and CMV Viruses Replication 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Other Patient Populations 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 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 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hepatotoxicity 17.2 Pancreatitis 17.3 Birth Defects and Neurobehavioral Development Adverse Effects 17.4 Suicidal Thinking and Behavior 17.5 Hyperammonemia 17.6 CNS depression 17.7 Multi-organ Hypersensitivity Reaction FDA-APPROVED MEDICATION GUIDE * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 3 of 57 FULL PRESCRIBING INFORMATION BOXED WARNING WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 4 of 57 warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. Because it may be a hazard to the fetus, Depakote should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment [see Warnings and Precautions (5.2) and Patient Counseling Information (17.3)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 5 of 57 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 6 of 57 Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 7 of 57 Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.13)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 8 of 57 Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose- related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.11)]. Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non- specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 9 of 57 these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Use in Women of Childbearing Potential Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, Depakote should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. 5.3 Birth Defects and Neurobehavioral Adverse Effects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 10 of 57 congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94 - 104]). The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development. In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and demonstrated behavioral deficits [see Use in Specific Populations (8.1)]. 5.4 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.5 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 11 of 57 deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.9)]. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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 Drug Patients Relative Risk: Incidence of Events in Risk Difference: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 12 of 57 with Events Per 1,000 Patients with Events Per 1,000 Patients Drug Patients/Incidence in Placebo Patients 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 Depakote 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. 5.7 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose- related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 13 of 57 5.8 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.10)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.10)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.5, 5.8)]. 5.10 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 14 of 57 5.11 Multi-organ Hypersensitivity Reaction Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.12 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.13 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 15 of 57 5.14 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.15 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.16 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 16 of 57 only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 17 of 57 Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo- treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 18 of 57 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 19 of 57 Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 20 of 57 Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 21 of 57 Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Other Patient Populations Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. Gastrointestinal The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients. CNS Effects Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)]. Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy. Dermatologic Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens- Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 22 of 57 epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7.2)]. Psychiatric Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal Weakness. Hematologic Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Hepatic Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose- related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions (5.1)]. Endocrine Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.15)]. There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established. Pancreatic Acute pancreatitis including fatalities [see Warnings and Precautions (5.4)]. Metabolic Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 23 of 57 Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia. Genitourinary Enuresis and urinary tract infection. Special Senses Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported. Other Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia. There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 24 of 57 The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β- oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.12)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 25 of 57 Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 26 of 57 Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co- administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 27 of 57 There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co- administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 28 of 57 Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D: [see Warnings and Precautions (5.3)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 29 of 57 All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. In animal studies, offspring had structural malformations similar to those seen in humans and demonstrated behavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • To prevent major seizures, women with epilepsy should not discontinue Depakote abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 30 of 57 • Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. • Patients taking valproate may develop hepatic failure [see Boxed Warning, Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% - 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other anti- epileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin, 99 [95% C.I. 94-104)]. The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 31 of 57 neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning, Warning and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 32 of 57 The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Nonclinical Developmental Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 33 of 57 A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 34 of 57 Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 35 of 57 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 36 of 57 influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 37 of 57 eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half- life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 38 of 57 The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility Carcinogenesis Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 39 of 57 incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 40 of 57 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 41 of 57 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. * p < 0.05 PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 42 of 57 In one multi-clinic, placebo-controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 43 of 57 Figure 2 The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post-randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 44 of 57 High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 45 of 57 Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 46 of 57 Figure 4. Mean 4-week Migraine Rates 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 47 of 57 Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Abbo-Pac® unit dose packages of 100……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide. 17.1 Hepatotoxicity Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. 17.2 Pancreatitis Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.4)]. 17.3 Birth Defects and Neurobehavioral Development Adverse Effects Prescribers should inform pregnant women and women of childbearing potential that use of Depakote during pregnancy increases the risk of birth defects and adverse effects on neurobehavioral development. Prescribers should advise women to use effective contraception while using valproate. When appropriate, prescribers should counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g. migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 48 of 57 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 Use in Specific Populations (8.1)]. 17.4 Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including Depakote, 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 the healthcare providers [see Warnings and Precautions (5.6)]. 17.5 Hyperammonemia Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8, 5.9)]. 17.6 CNS depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. 17.7 Multi-organ Hypersensitivity Reaction Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.11)]. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 49 of 57 Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Sprinkle Capsules DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking a Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: o nausea or vomiting that does not go away o loss of appetite o pain on the right side of your stomach (abdomen) o dark urine o swelling of your face o yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 50 of 57 2. Depakote or Depakene may harm your unborn baby. o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with Depakote or Depakene affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. o Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. o There may be other medicines to treat your condition that have a lower chance of birth defects. o All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception) unless you are planning to become pregnant. o Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: o severe stomach pain that you may also feel in your back o nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 51 of 57 Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. o 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 52 of 57 • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem call a urea cycle disorder What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non- prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Taking Depakote or Depakene 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. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 53 of 57 Know the medicines you take. Keep a list of them and show it your healthcare provider and pharmacist each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakote without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can not swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene may cause other serious side effects including: • Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 54 of 57 • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 950F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 55 of 57 These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C) • Store Depakote Delayed Release Tablets below 86°F (30°C) • Store Depakote Sprinkle Capsules between below 77°F (25°C) • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C) • Store Depakene Oral Solution below 86°F (30°C) Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene 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 Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbott.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote: Active ingredient: divalproex sodium Inactive ingredients: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 56 of 57 • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 500 mg is Mfd. by Abbott Laboratories, North Chicago, IL 60064 U.S.A. or Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 For Abbott Laboratories, North Chicago, IL 60064 U.S.A. Depakote Tablets: Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 57 of 57 For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Oral solution: Mfd. by Abbott Laboratories, North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Issued 10/2011 Abbott Laboratories This Medication Guide has been approved by the U.S. Food and Drug Administration. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:53.680741	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018723s037lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 40}
11,299	NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 1 of 57 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) Tablets for Oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years are at a considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and perform liver function tests prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects and other major malformations (5.2, 5.3) • Pancreatitis, including fatal hemorrhagic cases (5.4) -------RECENT MAJOR CHANGES------- Warnings and Precautions, Use in Women of Childbearing Potential (5.2) 10/2011 Warnings and Precautions, Birth Defects (5.3) 10/2011 -------INDICATIONS AND USAGE------- Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) -------DOSAGE AND ADMINISTRATION------- • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed. (2.1, 2.2) • Mania: Initial dose is 750 mg daily increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed. (2.3) -------DOSAGE FORMS AND STRENGTHS------- Tablets: 125 mg, 250mg and 500mg (3) -------CONTRAINDICATIONS------- • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known hypersensitivity to the drug (4, 5.11) • Urea cycle disorders (4, 5.5) -------WARNINGS AND PRECAUTIONS------- • Hepatotoxicity; monitor liver function tests (5.1) • Women of Childbearing Potential; weigh Depakote benefits of use during pregnancy against risk to the fetus (5.2) • Birth Defects; Depakote can cause fetal harm when taken during pregnancy (5.3) • Pancreatitis; Depakote should ordinarily be discontinued (5.4) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.6) • Thrombocytopenia; monitor platelet counts and coagulation tests (5.7) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.5, 5.8, 5.9) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.10) • Multi-organ hypersensitivity reaction; discontinue Depakote (5.11) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.13) -------ADVERSE REACTIONS------- • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, ambylopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss, (6.1, 6.2, 6.3). To report SUSPECTED ADVERSE REACTIONS, contact Abbott Laboratories at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------DRUG INTERACTIONS------- • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3) -------USE IN SPECIFIC POPULATIONS------- • Pregnancy: Depakote can cause congenital malformations including neural tube defects. Pregnancy registry available (5.2, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.13, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 10/2011 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 2 of 57 FULL PRESCRIBING INFORMATION: CONTENTS* BOXED WARNING 1 INDICATIONS AND USAGE 1.1 Mania 1.2 Epilepsy 1.3 Migraine 2 DOSAGE AND ADMINISTRATION 2.1 Mania 2.2 Epilepsy 2.3 Migraine 2.4 General Dosing Advice 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Use in Women of Childbearing Potential 5.3 Birth Defects and Neurobehavioral Adverse Effects 5.4 Pancreatitis 5.5 Urea Cycle Disorders 5.6 Suicidal Behavior and Ideation 5.7 Thrombocytopenia 5.8 Hyperammonemia 5.9 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use 5.10 Hypothermia 5.11 Multi-Organ Hypersensitivity Reactions 5.12 Interaction with Carbapenem Antibiotics 5.13 Somnolence in the Elderly 5.14 Monitoring: Drug Plasma Concentration 5.15 Effect on Ketone and Thyroid Function Tests 5.16 Effect on HIV and CMV Viruses Replication 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Other Patient Populations 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 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 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hepatotoxicity 17.2 Pancreatitis 17.3 Birth Defects and Neurobehavioral Development Adverse Effects 17.4 Suicidal Thinking and Behavior 17.5 Hyperammonemia 17.6 CNS depression 17.7 Multi-organ Hypersensitivity Reaction FDA-APPROVED MEDICATION GUIDE * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 3 of 57 FULL PRESCRIBING INFORMATION BOXED WARNING WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 4 of 57 warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. Because it may be a hazard to the fetus, Depakote should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment [see Warnings and Precautions (5.2) and Patient Counseling Information (17.3)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 5 of 57 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 6 of 57 Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 7 of 57 Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.13)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 8 of 57 Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose- related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.11)]. Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non- specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 9 of 57 these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Use in Women of Childbearing Potential Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, Depakote should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. 5.3 Birth Defects and Neurobehavioral Adverse Effects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 10 of 57 congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94 - 104]). The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development. In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and demonstrated behavioral deficits [see Use in Specific Populations (8.1)]. 5.4 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.5 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 11 of 57 deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.9)]. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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 Drug Patients Relative Risk: Incidence of Events in Risk Difference: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 12 of 57 with Events Per 1,000 Patients with Events Per 1,000 Patients Drug Patients/Incidence in Placebo Patients 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 Depakote 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. 5.7 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose- related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 13 of 57 5.8 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.10)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.10)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.5, 5.8)]. 5.10 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 14 of 57 5.11 Multi-organ Hypersensitivity Reaction Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.12 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.13 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 15 of 57 5.14 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.15 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.16 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 16 of 57 only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 17 of 57 Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo- treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 18 of 57 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 19 of 57 Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 20 of 57 Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 21 of 57 Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Other Patient Populations Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. Gastrointestinal The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients. CNS Effects Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)]. Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy. Dermatologic Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens- Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 22 of 57 epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7.2)]. Psychiatric Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal Weakness. Hematologic Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Hepatic Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose- related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions (5.1)]. Endocrine Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.15)]. There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established. Pancreatic Acute pancreatitis including fatalities [see Warnings and Precautions (5.4)]. Metabolic Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 23 of 57 Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia. Genitourinary Enuresis and urinary tract infection. Special Senses Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported. Other Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia. There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 24 of 57 The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β- oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.12)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 25 of 57 Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 26 of 57 Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co- administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 27 of 57 There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co- administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 28 of 57 Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D: [see Warnings and Precautions (5.3)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 29 of 57 All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. In animal studies, offspring had structural malformations similar to those seen in humans and demonstrated behavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • To prevent major seizures, women with epilepsy should not discontinue Depakote abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 30 of 57 • Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. • Patients taking valproate may develop hepatic failure [see Boxed Warning, Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% - 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other anti- epileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin, 99 [95% C.I. 94-104)]. The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 31 of 57 neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning, Warning and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 32 of 57 The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Nonclinical Developmental Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 33 of 57 A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 34 of 57 Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 35 of 57 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 36 of 57 influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 37 of 57 eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half- life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 38 of 57 The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility Carcinogenesis Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 39 of 57 incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 40 of 57 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 41 of 57 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. * p < 0.05 PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 42 of 57 In one multi-clinic, placebo-controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 43 of 57 Figure 2 The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post-randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 44 of 57 High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 45 of 57 Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 46 of 57 Figure 4. Mean 4-week Migraine Rates 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 47 of 57 Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Abbo-Pac® unit dose packages of 100……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide. 17.1 Hepatotoxicity Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. 17.2 Pancreatitis Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.4)]. 17.3 Birth Defects and Neurobehavioral Development Adverse Effects Prescribers should inform pregnant women and women of childbearing potential that use of Depakote during pregnancy increases the risk of birth defects and adverse effects on neurobehavioral development. Prescribers should advise women to use effective contraception while using valproate. When appropriate, prescribers should counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g. migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 48 of 57 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 Use in Specific Populations (8.1)]. 17.4 Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including Depakote, 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 the healthcare providers [see Warnings and Precautions (5.6)]. 17.5 Hyperammonemia Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8, 5.9)]. 17.6 CNS depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. 17.7 Multi-organ Hypersensitivity Reaction Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.11)]. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 49 of 57 Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Sprinkle Capsules DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking a Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: o nausea or vomiting that does not go away o loss of appetite o pain on the right side of your stomach (abdomen) o dark urine o swelling of your face o yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 50 of 57 2. Depakote or Depakene may harm your unborn baby. o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with Depakote or Depakene affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. o Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. o There may be other medicines to treat your condition that have a lower chance of birth defects. o All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception) unless you are planning to become pregnant. o Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: o severe stomach pain that you may also feel in your back o nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 51 of 57 Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. o 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 52 of 57 • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem call a urea cycle disorder What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non- prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Taking Depakote or Depakene 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. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 53 of 57 Know the medicines you take. Keep a list of them and show it your healthcare provider and pharmacist each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakote without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can not swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene may cause other serious side effects including: • Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 54 of 57 • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 950F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 55 of 57 These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C) • Store Depakote Delayed Release Tablets below 86°F (30°C) • Store Depakote Sprinkle Capsules between below 77°F (25°C) • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C) • Store Depakene Oral Solution below 86°F (30°C) Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene 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 Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbott.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote: Active ingredient: divalproex sodium Inactive ingredients: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 56 of 57 • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 500 mg is Mfd. by Abbott Laboratories, North Chicago, IL 60064 U.S.A. or Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 For Abbott Laboratories, North Chicago, IL 60064 U.S.A. Depakote Tablets: Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 57 of 57 For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Oral solution: Mfd. by Abbott Laboratories, North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Issued 10/2011 Abbott Laboratories This Medication Guide has been approved by the U.S. Food and Drug Administration. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:54.023471	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018723s037lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 45}
11,297	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) Tablets for Oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3, 5.4) • Pancreatitis, including fatal hemorrhagic cases (5.5) -------RECENT MAJOR CHANGES------ Boxed Warning, Hepatotoxicity 07/2013 Boxed Warning, Fetal Risk 06/2013 Indications and Usage, Important Limitations (1.4) 06/2013 Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013 Contraindications, Prophylaxis of Migraines in Pregnancy (4) 06/2013 Warnings and Precautions, Hepatotoxicity (5.1) 07/2013 Warnings and Precautions, Birth Defects (5.2) 06/2013 Warnings and Precautions, Decreased IQ (5.3) 06/2013 Warnings and Precautions, Use in Women of Childbearing Potential (5.4) 06/2013 -------INDICATIONS AND USAGE------- Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) -------DOSAGE AND ADMINISTRATION------ • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed (2.1, 2.2). • Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed (2.3). -------DOSAGE FORMS AND STRENGTHS------ Tablets: 125 mg, 250 mg and 500 mg (3) -------CONTRAINDICATIONS------ • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) (4, 5.1) • Suspected POLG-related disorder in children under two years of age (4, 5.1) • Known hypersensitivity to the drug (4, 5.12) • Urea cycle disorders (4, 5.6) • Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1) -------WARNINGS AND PRECAUTIONS------ • Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1) • Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4) • Pancreatitis; Depakote should ordinarily be discontinued (5.5) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.7) • Thrombocytopenia; monitor platelet counts and coagulation tests (5.8) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.6, 5.9, 5.10) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.11) • Multi-organ hypersensitivity reaction; discontinue Depakote (5.12) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14) -------ADVERSE REACTIONS------ • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, ambylopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3). • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------DRUG INTERACTIONS------ • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme- inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3) -------USE IN SPECIFIC POPULATIONS------ • Pregnancy: Depakote can cause congenital malformations including neural tube defects and decreased IQ. (5.2, 5.3, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.14, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 06/2014 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LIFE THREATENING ADVERSE REACTIONS 1.4 Important Limitations 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 1.1 Mania 2.1 Mania 1.2 Epilepsy 2.2 Epilepsy 1.3 Migraine 2.3 Migraine Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.4 General Dosing Advice 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Birth Defects 5.3 Decreased IQ Following in utero Exposure 5.4 Use in Women of Childbearing Potential 5.5 Pancreatitis 5.6 Urea Cycle Disorders 5.7 Suicidal Behavior and Ideation 5.8 Thrombocytopenia 5.9 Hyperammonemia 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use 5.11 Hypothermia 5.12 Multi-Organ Hypersensitivity Reactions 5.13 Interaction with Carbapenem Antibiotics 5.14 Somnolence in the Elderly 5.15 Monitoring: Drug Plasma Concentration 5.16 Effect on Ketone and Thyroid Function Tests 5.17 Effect on HIV and CMV Viruses Replication 5.18 Medication Residue in the Stool 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hepatotoxicity 17.2 Pancreatitis 17.3 Birth Defects and Decreased IQ 17.4 Suicidal Thinking and Behavior 17.5 Hyperammonemia 17.6 CNS Depression 17.7 Multi-Organ Hypersensitivity Reactions 17.8 Medication Residue in the Stool MEDICATION GUIDE Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3528395 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 ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3, 5.4)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.5)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. 1.4 Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1), and Patient Counseling Information (17.3)]. Depakote is contraindicated for prophylaxis of migraine headaches in women who are pregnant. 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Simple and Complex Absence Seizures Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS • Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.12)]. • Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.6)]. • Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers- Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Birth Defects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.3 Decreased IQ Following in utero Exposure Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1)]. Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. 5.4 Use in Women of Childbearing Potential Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.5 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.6 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)]. 5.7 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 Depakote 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. 5.8 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. 5.9 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6, 5.10)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.6, 5.9)]. 5.11 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.12 Multi-Organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.13 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.14 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.15 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.16 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.17 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 5.18 Medication Residue in the Stool There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Post-Marketing Experience The following adverse reactions have been identified during post approval use of Depakote. 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. Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens- Johnson syndrome. Psychiatric: Emotional upset, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness. Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion. Genitourinary: Enuresis and urinary tract infection. Special Senses: Hearing loss. Other: Allergic reaction, anaphylaxis, developmental delay, autism and/or autism spectrum disorder, bone pain, bradycardia, and cutaneous vasculitis. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11 epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Olanzapine Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine. Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions (5.2, 5.3)]. Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. • Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: • Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). • Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. • Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. • To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. • Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. • Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Juvenile Animal Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4) and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. Figure 1 p < 0.05 PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Figure 2 Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post- randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty- seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Figure 4 Mean 4-week Migraine Rates Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 15 REFERENCES 1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Unit Dose Packages of 100.................………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Unit Dose Packages of 100................………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Unit Dose Packages of 100................……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide. 17.1 Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. 17.2 Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.5)]. 17.3 Birth Defects and Decreased IQ Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)]. Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant. Encourage patients 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 Use in Specific Populations (8.1)]. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17.4 Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including Depakote, 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. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.7)]. 17.5 Hyperammonemia Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)]. 17.6 CNS Depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. 17.7 Multi-Organ Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.12)]. 17.8 Medication Residue in the Stool Instruct patients to notify their healthcare provider if they notice a medication residue in the stool [see Warnings and Precautions (5.18)]. Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Tablets DEPAKOTE (dep-a-kOte) Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (divalproex sodium) Sprinkle Capsules DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: o nausea or vomiting that does not go away o loss of appetite o pain on the right side of your stomach (abdomen) o dark urine o swelling of your face o yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. 2. Depakote or Depakene may harm your unborn baby. o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with Depakote or Depakene affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. o Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. o There may be other medicines to treat your condition that have a lower chance of causing birth defects and decreased IQ in your child. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda o Women who are pregnant must not take Depakote or Depakene to prevent migraine headaches. o All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception). o Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: o severe stomach pain that you may also feel in your back o nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. o 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). Reference ID: 3528395 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem called urea cycle disorder • are pregnant for the prevention of migraine headaches What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Taking Depakote or Depakene 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 each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can not swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene can cause serious side effects including: • Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose. • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C). • Store Depakote Delayed Release Tablets below 86°F (30°C). • Store Depakote Sprinkle Capsules below 77°F (25°C). • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C). • Store Depakene Oral Solution below 86°F (30°C). Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depakote or Depakene 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 Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbvie.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote: Active ingredient: divalproex sodium Inactive ingredients: • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617 500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or AbbVie LTD, Barceloneta, PR 00617 Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For AbbVie Inc., North Chicago, IL 60064 U.S.A. Depakote Tablets: Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Oral Solution: Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. This Medication Guide has been approved by the U.S. Food and Drug Administration. 03-AXXX June 2014 Reference ID: 3528395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:54.158922	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018723s041lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 41}
11,300	NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 1 of 57 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) Tablets for Oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years are at a considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and perform liver function tests prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects and other major malformations (5.2, 5.3) • Pancreatitis, including fatal hemorrhagic cases (5.4) -------RECENT MAJOR CHANGES------- Warnings and Precautions, Use in Women of Childbearing Potential (5.2) 10/2011 Warnings and Precautions, Birth Defects (5.3) 10/2011 -------INDICATIONS AND USAGE------- Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) -------DOSAGE AND ADMINISTRATION------- • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed. (2.1, 2.2) • Mania: Initial dose is 750 mg daily increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2) • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed. (2.3) -------DOSAGE FORMS AND STRENGTHS------- Tablets: 125 mg, 250mg and 500mg (3) -------CONTRAINDICATIONS------- • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known hypersensitivity to the drug (4, 5.11) • Urea cycle disorders (4, 5.5) -------WARNINGS AND PRECAUTIONS------- • Hepatotoxicity; monitor liver function tests (5.1) • Women of Childbearing Potential; weigh Depakote benefits of use during pregnancy against risk to the fetus (5.2) • Birth Defects; Depakote can cause fetal harm when taken during pregnancy (5.3) • Pancreatitis; Depakote should ordinarily be discontinued (5.4) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.6) • Thrombocytopenia; monitor platelet counts and coagulation tests (5.7) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.5, 5.8, 5.9) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.10) • Multi-organ hypersensitivity reaction; discontinue Depakote (5.11) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.13) -------ADVERSE REACTIONS------- • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, ambylopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss, (6.1, 6.2, 6.3). To report SUSPECTED ADVERSE REACTIONS, contact Abbott Laboratories at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------DRUG INTERACTIONS------- • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3) -------USE IN SPECIFIC POPULATIONS------- • Pregnancy: Depakote can cause congenital malformations including neural tube defects. Pregnancy registry available (5.2, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.13, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 10/2011 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 2 of 57 FULL PRESCRIBING INFORMATION: CONTENTS* BOXED WARNING 1 INDICATIONS AND USAGE 1.1 Mania 1.2 Epilepsy 1.3 Migraine 2 DOSAGE AND ADMINISTRATION 2.1 Mania 2.2 Epilepsy 2.3 Migraine 2.4 General Dosing Advice 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Use in Women of Childbearing Potential 5.3 Birth Defects and Neurobehavioral Adverse Effects 5.4 Pancreatitis 5.5 Urea Cycle Disorders 5.6 Suicidal Behavior and Ideation 5.7 Thrombocytopenia 5.8 Hyperammonemia 5.9 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use 5.10 Hypothermia 5.11 Multi-Organ Hypersensitivity Reactions 5.12 Interaction with Carbapenem Antibiotics 5.13 Somnolence in the Elderly 5.14 Monitoring: Drug Plasma Concentration 5.15 Effect on Ketone and Thyroid Function Tests 5.16 Effect on HIV and CMV Viruses Replication 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Other Patient Populations 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 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 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hepatotoxicity 17.2 Pancreatitis 17.3 Birth Defects and Neurobehavioral Development Adverse Effects 17.4 Suicidal Thinking and Behavior 17.5 Hyperammonemia 17.6 CNS depression 17.7 Multi-organ Hypersensitivity Reaction FDA-APPROVED MEDICATION GUIDE * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 3 of 57 FULL PRESCRIBING INFORMATION BOXED WARNING WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 4 of 57 warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. Because it may be a hazard to the fetus, Depakote should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment [see Warnings and Precautions (5.2) and Patient Counseling Information (17.3)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 5 of 57 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 6 of 57 Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 7 of 57 Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.13)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 8 of 57 Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose- related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.11)]. Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non- specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 9 of 57 these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Use in Women of Childbearing Potential Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, Depakote should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. 5.3 Birth Defects and Neurobehavioral Adverse Effects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 10 of 57 congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94 - 104]). The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development. In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and demonstrated behavioral deficits [see Use in Specific Populations (8.1)]. 5.4 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.5 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 11 of 57 deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.9)]. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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 Drug Patients Relative Risk: Incidence of Events in Risk Difference: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 12 of 57 with Events Per 1,000 Patients with Events Per 1,000 Patients Drug Patients/Incidence in Placebo Patients 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 Depakote 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. 5.7 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose- related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 13 of 57 5.8 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.10)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.10)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.5, 5.8)]. 5.10 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 14 of 57 5.11 Multi-organ Hypersensitivity Reaction Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.12 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.13 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 15 of 57 5.14 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.15 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.16 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 16 of 57 only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 17 of 57 Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo- treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 18 of 57 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 19 of 57 Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 20 of 57 Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 21 of 57 Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Other Patient Populations Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. Gastrointestinal The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients. CNS Effects Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)]. Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy. Dermatologic Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens- Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 22 of 57 epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7.2)]. Psychiatric Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal Weakness. Hematologic Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Hepatic Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose- related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions (5.1)]. Endocrine Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.15)]. There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established. Pancreatic Acute pancreatitis including fatalities [see Warnings and Precautions (5.4)]. Metabolic Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 23 of 57 Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia. Genitourinary Enuresis and urinary tract infection. Special Senses Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported. Other Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia. There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 24 of 57 The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β- oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.12)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 25 of 57 Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 26 of 57 Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co- administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 27 of 57 There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co- administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 28 of 57 Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D: [see Warnings and Precautions (5.3)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 29 of 57 All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. In animal studies, offspring had structural malformations similar to those seen in humans and demonstrated behavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • To prevent major seizures, women with epilepsy should not discontinue Depakote abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 30 of 57 • Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. • Patients taking valproate may develop hepatic failure [see Boxed Warning, Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% - 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other anti- epileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin, 99 [95% C.I. 94-104)]. The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 31 of 57 neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning, Warning and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 32 of 57 The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Nonclinical Developmental Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 33 of 57 A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 34 of 57 Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 35 of 57 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 36 of 57 influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 37 of 57 eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half- life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 38 of 57 The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility Carcinogenesis Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 39 of 57 incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 40 of 57 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 41 of 57 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. * p < 0.05 PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 42 of 57 In one multi-clinic, placebo-controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 43 of 57 Figure 2 The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post-randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 44 of 57 High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 45 of 57 Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 46 of 57 Figure 4. Mean 4-week Migraine Rates 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 47 of 57 Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Abbo-Pac® unit dose packages of 100……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide. 17.1 Hepatotoxicity Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. 17.2 Pancreatitis Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.4)]. 17.3 Birth Defects and Neurobehavioral Development Adverse Effects Prescribers should inform pregnant women and women of childbearing potential that use of Depakote during pregnancy increases the risk of birth defects and adverse effects on neurobehavioral development. Prescribers should advise women to use effective contraception while using valproate. When appropriate, prescribers should counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g. migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 48 of 57 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 Use in Specific Populations (8.1)]. 17.4 Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including Depakote, 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 the healthcare providers [see Warnings and Precautions (5.6)]. 17.5 Hyperammonemia Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8, 5.9)]. 17.6 CNS depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. 17.7 Multi-organ Hypersensitivity Reaction Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.11)]. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 49 of 57 Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Sprinkle Capsules DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking a Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: o nausea or vomiting that does not go away o loss of appetite o pain on the right side of your stomach (abdomen) o dark urine o swelling of your face o yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 50 of 57 2. Depakote or Depakene may harm your unborn baby. o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with Depakote or Depakene affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. o Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. o There may be other medicines to treat your condition that have a lower chance of birth defects. o All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception) unless you are planning to become pregnant. o Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: o severe stomach pain that you may also feel in your back o nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 51 of 57 Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. o 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 52 of 57 • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem call a urea cycle disorder What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non- prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Taking Depakote or Depakene 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. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 53 of 57 Know the medicines you take. Keep a list of them and show it your healthcare provider and pharmacist each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakote without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can not swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene may cause other serious side effects including: • Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 54 of 57 • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 950F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 55 of 57 These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C) • Store Depakote Delayed Release Tablets below 86°F (30°C) • Store Depakote Sprinkle Capsules between below 77°F (25°C) • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C) • Store Depakene Oral Solution below 86°F (30°C) Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene 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 Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbott.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote: Active ingredient: divalproex sodium Inactive ingredients: Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 56 of 57 • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 500 mg is Mfd. by Abbott Laboratories, North Chicago, IL 60064 U.S.A. or Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 For Abbott Laboratories, North Chicago, IL 60064 U.S.A. Depakote Tablets: Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 018723/S-037/S-040/S-043/S-045/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011 Page 57 of 57 For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Oral solution: Mfd. by Abbott Laboratories, North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Issued 10/2011 Abbott Laboratories This Medication Guide has been approved by the U.S. Food and Drug Administration. Reference ID: 3026475 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:54.509461	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018723s037lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 46}
11,301	• • • • • • • • • • • • • • • • HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) Tablets for Oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years are at a considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and perform liver function tests prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects and other major malformations (5.2, 5.3) • Pancreatitis, including fatal hemorrhagic cases (5.4) -------RECENT MAJOR CHANGES------ Warnings and Precautions, Use in Women of Childbearing Potential (5.2) 02/2013 Warnings and Precautions, Birth Defects (5.3) 02/2013 Warnings and Precautions, Medication Residue in the Stool (5.17) 02/2013 -------INDICATIONS AND USAGE------- Depakote is an anti-epileptic drug indicated for: Treatment of manic episodes associated with bipolar disorder (1.1) Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) Prophylaxis of migraine headaches (1.3) -------DOSAGE AND ADMINISTRATION------ Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed (2.1, 2.2). Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed (2.3). -------DOSAGE FORMS AND STRENGTHS------ Tablets: 125 mg, 250 mg and 500 mg (3) -------CONTRAINDICATIONS------ • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known hypersensitivity to the drug (4, 5.11) • Urea cycle disorders (4, 5.5) -------WARNINGS AND PRECAUTIONS------ • Hepatotoxicity; monitor liver function tests (5.1) • Women of Childbearing Potential; weigh Depakote benefits of use during pregnancy against risk to the fetus (5.2) • Birth Defects; Depakote can cause fetal harm when taken during pregnancy (5.3) • Pancreatitis; Depakote should ordinarily be discontinued (5.4) Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.6) Thrombocytopenia; monitor platelet counts and coagulation tests (5.7) Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.5, 5.8, 5.9) Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.10) Multi-organ hypersensitivity reaction; discontinue Depakote (5.11) Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.13) -------ADVERSE REACTIONS------ Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, ambylopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3). The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4). To report SUSPECTED ADVERSE REACTIONS, contact Abbott Laboratories at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------DRUG INTERACTIONS------ • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3) -------USE IN SPECIFIC POPULATIONS------ • Pregnancy: Depakote can cause congenital malformations including neural tube defects. Pregnancy registry available (5.2, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.13, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 02/2013 FULL PRESCRIBING INFORMATION: CONTENTS* BOXED WARNING 1 INDICATIONS AND USAGE 1.1 Mania 1.2 Epilepsy 1.3 Migraine 2 DOSAGE AND ADMINISTRATION 2.1 Mania 2.2 Epilepsy 2.3 Migraine 2.4 General Dosing Advice Reference ID: 3268091 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Use in Women of Childbearing Potential 5.3 Birth Defects and Neurobehavioral Adverse Effects 5.4 Pancreatitis 5.5 Urea Cycle Disorders 5.6 Suicidal Behavior and Ideation 5.7 Thrombocytopenia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.8 Hyperammonemia 5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use 5.10 Hypothermia 5.11 Multi-Organ Hypersensitivity Reactions 5.12 Interaction with Carbapenem Antibiotics 5.13 Somnolence in the Elderly 5.14 Monitoring: Drug Plasma Concentration 5.15 Effect on Ketone and Thyroid Function Tests 5.16 Effect on HIV and CMV Viruses Replication 5.17 Medication Residue in the Stool 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Other Patient Populations 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hepatotoxicity 17.2 Pancreatitis 17.3 Birth Defects and Neurobehavioral Development Adverse Effects 17.4 Suicidal Thinking and Behavior 17.5 Hyperammonemia 17.6 CNS depression 17.7 Multi-Organ Hypersensitivity Reactions 17.8 Medication Residue in the Stool MEDICATION GUIDE * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION BOXED WARNING WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.4)]. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. Because it may be a hazard to the fetus, Depakote should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment [see Warnings and Precautions (5.2) and Patient Counseling Information (17.3)]. 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose- related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 CONTRAINDICATIONS Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.11)]. Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Use in Women of Childbearing Potential Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, Depakote should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. 5.3 Birth Defects and Neurobehavioral Adverse Effects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94-104]). The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development. In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and demonstrated behavioral deficits [see Use in Specific Populations (8.1)]. 5.4 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.5 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.9)]. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 Depakote 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. 5.7 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose- related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.8 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.10)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.10)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.5, 5.8)]. 5.10 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.11 Multi-Organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.12 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.13 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. 5.14 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.15 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.16 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 5.17 Medication Residue in the Stool There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo- treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) Low Dose (%) Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (n = 131) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Other Patient Populations Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. Gastrointestinal The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients. CNS Effects Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)]. Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy. Dermatologic Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens- Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7.2)]. Psychiatric Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal Weakness. Hematologic Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Hepatic Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose- related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions (5.1)]. Endocrine Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.15)]. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established. Pancreatic Acute pancreatitis including fatalities [see Warnings and Precautions (5.4)]. Metabolic Hyperammonemia [see Warnings and Precautions (5.8, 5.9)], hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia. Genitourinary Enuresis and urinary tract infection. Special Senses Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported. Other Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia [see Warnings and Precautions (5.10)]. There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.12)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category D [see Warnings and Precautions (5.3)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. In animal studies, offspring had structural malformations similar to those seen in humans and demonstrated behavioral deficits. Clinical Considerations Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • To prevent major seizures, women with epilepsy should not discontinue Depakote abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. • Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. • Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin, (99 [95% C.I. 94-104]). The D.A.S., which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ testing and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Nonclinical Developmental Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half- life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4) and Warnings and Precautions (5.1)]. Renal Disease Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. Figure 1 * p < 0.05 PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Figure 2 The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post-randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda graph 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Figure 4 Mean 4-week Migraine Rates Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Abbo-Pac® unit dose packages of 100………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Abbo-Pac® unit dose packages of 100……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide. 17.1 Hepatotoxicity Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. 17.2 Pancreatitis Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.4)]. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17.3 Birth Defects and Neurobehavioral Development Adverse Effects Prescribers should inform pregnant women and women of childbearing potential that use of Depakote during pregnancy increases the risk of birth defects and adverse effects on neurobehavioral development. Prescribers should advise women to use effective contraception while using valproate. When appropriate, prescribers should counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g. migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. 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 Use in Specific Populations (8.1)]. 17.4 Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including Depakote, 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 the healthcare providers [see Warnings and Precautions (5.6)]. 17.5 Hyperammonemia Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8, 5.9)]. 17.6 CNS depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. 17.7 Multi-Organ Hypersensitivity Reactions Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.11)]. 17.8 Medication Residue in the Stool Patients should be instructed to notify their healthcare provider if they notice a medication residue in the stool [see Warnings and Precautions (5.17)]. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Sprinkle Capsules DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: o nausea or vomiting that does not go away o loss of appetite o pain on the right side of your stomach (abdomen) Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda o dark urine o swelling of your face o yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. 2. Depakote or Depakene may harm your unborn baby. o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with Depakote or Depakene affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. o Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. o There may be other medicines to treat your condition that have a lower chance of birth defects. o All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception) unless you are planning to become pregnant. o Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: o severe stomach pain that you may also feel in your back o nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. o 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem call a urea cycle disorder What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Taking Depakote or Depakene 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 each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakote without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can not swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene can cause serious side effects including: • Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose. • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C) • Store Depakote Delayed Release Tablets below 86°F (30°C) • Store Depakote Sprinkle Capsules below 77°F (25°C) • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C) • Store Depakene Oral Solution below 86°F (30°C) Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene 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 Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbott.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote Active ingredient: divalproex sodium Inactive ingredients: • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 500 mg is Mfd. by Abbott Laboratories, North Chicago, IL 60064 U.S.A. or Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 For Abbott Laboratories, North Chicago, IL 60064 U.S.A. Depakote Tablets: Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617 For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Depakene Oral solution: Mfd. by Abbott Laboratories, North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For Abbott Laboratories, North Chicago, IL 60064, U.S.A. Issued 02/2013 Abbott Laboratories This Medication Guide has been approved by the U.S. Food and Drug Administration. Reference ID: 3268091 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:54.539960	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018723s047lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 47}
11,302	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) Tablets for Oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3, 5.4) • Pancreatitis, including fatal hemorrhagic cases (5.5) -------RECENT MAJOR CHANGES------- Boxed Warning, Hepatotoxicity 07/2013 Boxed Warning, Fetal Risk 06/2013 Indications and Usage, Important Limitations (1.2) 06/2013 Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013 Contraindications, Prophylaxis of Migraines in Pregnancy (4) 06/2013 Warnings and Precautions, Hepatotoxicity (5.1) 07/2013 Warnings and Precautions, Birth Defects (5.2) 06/2013 Warnings and Precautions, Decreased IQ (5.3) 06/2013 Warnings and Precautions, Use in Women of Childbearing Potential (5.4) 06/2013 Warnings and Precautions, Medication Residue in the Stool (5.18) 02/2013 -------INDICATIONS AND USAGE------- Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) -------DOSAGE AND ADMINISTRATION------- • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed (2.1, 2.2). • Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed (2.3). -------DOSAGE FORMS AND STRENGTHS------- Tablets: 125 mg, 250 mg and 500 mg (3) -------CONTRAINDICATIONS------- • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) (4, 5.1) • Suspected POLG-related disorder in children under two years of age (4, 5.1) • Known hypersensitivity to the drug (4, 5.12) • Urea cycle disorders (4, 5.6) • Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1) -------WARNINGS AND PRECAUTIONS------- • Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1) • Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4) • Pancreatitis; Depakote should ordinarily be discontinued (5.5) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.7) • Thrombocytopenia; monitor platelet counts and coagulation tests (5.8) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.6, 5.9, 5.10) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.11) • Multi-organ hypersensitivity reaction; discontinue Depakote (5.12) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14) -------ADVERSE REACTIONS------- • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, ambylopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3). • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------DRUG INTERACTIONS------- • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme- inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3) -------USE IN SPECIFIC POPULATIONS------- • Pregnancy: Depakote can cause congenital malformations including neural tube defects and decreased IQ. (5.2, 5.3, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.14, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 07/2013 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LIFE THREATENING ADVERSE REACTIONS 1 INDICATIONS AND USAGE 1.1 Mania 1.2 Epilepsy 1.3 Migraine 1.4 Important Limitations 2 DOSAGE AND ADMINISTRATION 2.1 Mania 2.2 Epilepsy 2.3 Migraine 2.4 General Dosing Advice 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.1 Hepatotoxicity 5.2 Birth Defects 5.3 Decreased IQ Following in utero Exposure 5.4 Use in Women of Childbearing Potential 5.5 Pancreatitis 5.6 Urea Cycle Disorders 5.7 Suicidal Behavior and Ideation 5.8 Thrombocytopenia 5.9 Hyperammonemia 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use 5.11 Hypothermia 5.12 Multi-Organ Hypersensitivity Reactions 5.13 Interaction with Carbapenem Antibiotics 5.14 Somnolence in the Elderly 5.15 Monitoring: Drug Plasma Concentration 5.16 Effect on Ketone and Thyroid Function Tests 5.17 Effect on HIV and CMV Viruses Replication 5.18 Medication Residue in the Stool 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Other Patient Populations 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hepatotoxicity 17.2 Pancreatitis 17.3 Birth Defects and Decreased IQ 17.4 Suicidal Thinking and Behavior 17.5 Hyperammonemia 17.6 CNS Depression 17.7 Multi-Organ Hypersensitivity Reactions 17.8 Medication Residue in the Stool MEDICATION GUIDE * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3349699 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 ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions (5.1)]. Fetal Risk Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3, 5.4)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.5)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. 1.4 Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1), and Patient Counseling Information (17.3)]. Depakote is contraindicated for prophylaxis of migraine headaches in women who are pregnant. 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Reference ID: 3349699 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 to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS • Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions (5.1)]. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.12)]. • Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.6)]. • Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers- Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Birth Defects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.3 Decreased IQ Following in utero Exposure Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1)]. Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. 5.4 Use in Women of Childbearing Potential Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. 5.5 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.6 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)]. 5.7 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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: 3349699 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 Depakote 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. 5.8 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. 5.9 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6, 5.10)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.6, 5.9)]. 5.11 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.12 Multi-Organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.13 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.14 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. 5.15 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.16 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.17 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 5.18 Medication Residue in the Stool There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote- treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote- treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo- Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Back pain 8% 6% Alopecia 7% 1% Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Other Patient Populations Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. Gastrointestinal The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CNS Effects Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions (5.6)]. Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy. Dermatologic Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7.2)]. Psychiatric Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal Weakness. Hematologic Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Hepatic Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions (5.1)]. Endocrine Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)]. There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established. Pancreatic Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)]. Metabolic Hyperammonemia [see Warnings and Precautions (5.9, 5.10)], hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia. Genitourinary Enuresis and urinary tract infection. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Special Senses Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported. Other Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia [see Warnings and Precautions (5.11)]. There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH- valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co- administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11- epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11)]. Reference ID: 3349699 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 D for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions (5.2 and 5.3)]. Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. • Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: • Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). • Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. • Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. • To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. • Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Juvenile Animal Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. Reference ID: 3349699 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 No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elderly The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4) and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation- carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. Figure 1 * p < 0.05 Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Figure 2 Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post- randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty- seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Figure 4 Mean 4-week Migraine Rates 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 15 REFERENCES 1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252. Reference ID: 3349699 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 Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Unit Dose Packages of 100.................………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Unit Dose Packages of 100................………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Unit Dose Packages of 100................……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide. 17.1 Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17.2 Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.5)]. 17.3 Birth Defects and Decreased IQ Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)]. Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant. Encourage patients 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 Use in Specific Populations (8.1)]. 17.4 Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including Depakote, 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. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.7)]. 17.5 Hyperammonemia Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)]. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17.6 CNS Depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. 17.7 Multi-Organ Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.12)]. 17.8 Medication Residue in the Stool Instruct patients to notify their healthcare provider if they notice a medication residue in the stool [see Warnings and Precautions (5.18)]. Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Sprinkle Capsules DEPAKENE (dep-a-keen) Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: o nausea or vomiting that does not go away o loss of appetite o pain on the right side of your stomach (abdomen) o dark urine o swelling of your face o yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. 2. Depakote or Depakene may harm your unborn baby. o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with Depakote or Depakene affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda o Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. o There may be other medicines to treat your condition that have a lower chance of causing birth defects and decreased IQ in your child. o Women who are pregnant must not take Depakote or Depakene to prevent migraine headaches. o All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception). o Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1- 888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: o severe stomach pain that you may also feel in your back o nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. o 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: • to treat manic episodes associated with bipolar disorder Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem called urea cycle disorder • are pregnant for the prevention of migraine headaches What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Reference ID: 3349699 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, herbal supplements and medicines that you take for a short period of time. Taking Depakote or Depakene 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 each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakote without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can not swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene can cause serious side effects including: • Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose. • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C) • Store Depakote Delayed Release Tablets below 86°F (30°C) • Store Depakote Sprinkle Capsules below 77°F (25°C) • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C) • Store Depakene Oral Solution below 86°F (30°C) Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene to other people, even if they have the same symptoms that you have. It may harm them. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This Medication Guide summarizes the most important information about Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbvie.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote Active ingredient: divalproex sodium Inactive ingredients: • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617 500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064 U.S.A. Depakote Tablets: Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Oral Solution: Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. This Medication Guide has been approved by the U.S. Food and Drug Administration. Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 03-A815 July 2013 Reference ID: 3349699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:54.904446	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018723s048lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 48}
11,303	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) tablets, for oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3, 5.4) • Pancreatitis, including fatal hemorrhagic cases (5.5) ----------------------------INDICATIONS AND USAGE--------------------------- Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) -----------------------DOSAGE AND ADMINISTRATION---------------------- • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed (2.1, 2.2). • Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed (2.3). ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Tablets: 125 mg, 250 mg and 500 mg (3) ------------------------------CONTRAINDICATIONS------------------------------ • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) (4, 5.1) • Suspected POLG-related disorder in children under two years of age (4, 5.1) • Known hypersensitivity to the drug (4, 5.12) • Urea cycle disorders (4, 5.6) • Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1) • Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4) • Pancreatitis; Depakote should ordinarily be discontinued (5.5) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.7) • Thrombocytopenia; monitor platelet counts and coagulation tests (5.8) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.6, 5.9, 5.10) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.11) • Multi-organ hypersensitivity reaction; discontinue Depakote (5.12) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14) ------------------------------ADVERSE REACTIONS------------------------------ • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3). • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------------------------------DRUG INTERACTIONS----------------------------- • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme- inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3) ------------------------USE IN SPECIFIC POPULATIONS---------------------- • Pregnancy: Depakote can cause congenital malformations including neural tube defects and decreased IQ. (5.2, 5.3, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.14, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2014 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LIFE THREATENING ADVERSE REACTIONS 2.4 General Dosing Advice 1 INDICATIONS AND USAGE 3 DOSAGE FORMS AND STRENGTHS 1.1 Mania 4 CONTRAINDICATIONS 1.2 Epilepsy 5 WARNINGS AND PRECAUTIONS 1.3 Migraine 5.1 Hepatotoxicity 1.4 Important Limitations 5.2 Birth Defects 2 DOSAGE AND ADMINISTRATION 5.3 Decreased IQ Following in utero Exposure 2.1 Mania 5.4 Use in Women of Childbearing Potential 2.2 Epilepsy 5.5 Pancreatitis 2.3 Migraine 5.6 Urea Cycle Disorders Reference ID: 3660954 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.7 Suicidal Behavior and Ideation 5.8 Thrombocytopenia 5.9 Hyperammonemia 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use 5.11 Hypothermia 5.12 Multi-Organ Hypersensitivity Reactions 5.13 Interaction with Carbapenem Antibiotics 5.14 Somnolence in the Elderly 5.15 Monitoring: Drug Plasma Concentration 5.16 Effect on Ketone and Thyroid Function Tests 5.17 Effect on HIV and CMV Viruses Replication 5.18 Medication Residue in the Stool 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hepatotoxicity 17.2 Pancreatitis 17.3 Birth Defects and Decreased IQ 17.4 Suicidal Thinking and Behavior 17.5 Hyperammonemia 17.6 CNS Depression 17.7 Multi-Organ Hypersensitivity Reactions 17.8 Medication Residue in the Stool MEDICATION GUIDE Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3660954 2 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 ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug Reference ID: 3660954 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3, 5.4)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.5)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. Reference ID: 3660954 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. 1.4 Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1), and Patient Counseling Information (17.3)]. Depakote is contraindicated for prophylaxis of migraine headaches in women who are pregnant. 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Reference ID: 3660954 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Simple and Complex Absence Seizures Reference ID: 3660954 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Reference ID: 3660954 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS • Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.12)]. • Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.6)]. • Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and Reference ID: 3660954 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers- Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Birth Defects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Reference ID: 3660954 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.3 Decreased IQ Following in utero Exposure Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1)]. Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. 5.4 Use in Women of Childbearing Potential Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3660954 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.5 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.6 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)]. 5.7 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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. Reference ID: 3660954 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 Depakote 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. 5.8 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase Reference ID: 3660954 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. 5.9 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6, 5.10)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.6, 5.9)]. 5.11 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant Reference ID: 3660954 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.12 Multi-Organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.13 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.14 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. Reference ID: 3660954 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.15 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.16 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.17 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 5.18 Medication Residue in the Stool There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The following serious adverse reactions are described below and elsewhere in the labeling:  Hepatic failure [see Warnings and Precautions (5.1)]  Birth defects [see Warnings and Precautions (5.2)]  Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]  Pancreatitis [see Warnings and Precautions (5.5)]  Hyperammonemic encephalopathy [see Warnings and Precautions (5.6), (5.9), (5.10)]  Suicidal behavior and ideation [see Warnings and Precautions (5.7)] Reference ID: 3660954 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Thrombocytopenia [see Warnings and Precautions (5.8)]  Hypothermia [see Warnings and Precuations (5.11)]  Multi-organ hypersensitivity reactions [see Warnings and Precautions (5.12)]  Somnolence in the elderly [see Warnings and Precautions (5.14)] 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Reference ID: 3660954 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Reference ID: 3660954 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Reference ID: 3660954 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Reference ID: 3660954 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Reference ID: 3660954 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tremor 9% 0% Other Weight gain 8% 2% Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Post-Marketing Experience The following adverse reactions have been identified during post approval use of Depakote. 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. Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens- Johnson syndrome. Psychiatric: Emotional upset, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Neurologic: There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation. Reference ID: 3660954 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness. Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion. Genitourinary: Enuresis and urinary tract infection. Special Senses: Hearing loss. Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on Reference ID: 3660954 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. Reference ID: 3660954 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11 epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of Reference ID: 3660954 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Reference ID: 3660954 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Olanzapine No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine. Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions (5.2, 5.3)]. Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)]. Pregnancy Registry Reference ID: 3660954 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see Warnings and Precautions (5.3)]. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. An observational study has suggested that exposure to valproate products during pregnancy may increase the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. • Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: • Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Reference ID: 3660954 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. • Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. • To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. • Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. • Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 Reference ID: 3660954 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has Reference ID: 3660954 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Juvenile Animal Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate Reference ID: 3660954 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Reference ID: 3660954 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate Reference ID: 3660954 32 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Reference ID: 3660954 33 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days Reference ID: 3660954 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4) and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Reference ID: 3660954 35 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Reference ID: 3660954 36 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Reference ID: 3660954 37 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. Figure 1 p < 0.05 PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. Reference ID: 3660954 38 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Figure 2 Reference ID: 3660954 39 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post- randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Reference ID: 3660954 40 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. Reference ID: 3660954 41 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty- seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Figure 4 Mean 4-week Migraine Rates Reference ID: 3660954 42 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 15 REFERENCES 1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Unit Dose Packages of 100.................………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Reference ID: 3660954 43 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Unit Dose Packages of 100................………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Unit Dose Packages of 100................……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). 17.1 Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. 17.2 Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.5)]. 17.3 Birth Defects and Decreased IQ Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)]. Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant. Encourage patients 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 Use in Specific Populations (8.1)]. Reference ID: 3660954 44 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17.4 Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including Depakote, 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. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.7)]. 17.5 Hyperammonemia Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)]. 17.6 CNS Depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. 17.7 Multi-Organ Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.12)]. 17.8 Medication Residue in the Stool Instruct patients to notify their healthcare provider if they notice a medication residue in the stool [see Warnings and Precautions (5.18)]. Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Tablets DEPAKOTE (dep-a-kOte) Reference ID: 3660954 45 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (divalproex sodium delayed release capsules) Sprinkle Capsules DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: o nausea or vomiting that does not go away o loss of appetite o pain on the right side of your stomach (abdomen) o dark urine o swelling of your face o yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. 2. Depakote or Depakene may harm your unborn baby. o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with Depakote or Depakene affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. o Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. o There may be other medicines to treat your condition that have a lower chance of causing birth defects and decreased IQ in your child. Reference ID: 3660954 46 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda o Women who are pregnant must not take Depakote or Depakene to prevent migraine headaches. o All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception). o Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: o severe stomach pain that you may also feel in your back o nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. o 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). Reference ID: 3660954 47 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem called urea cycle disorder • are pregnant for the prevention of migraine headaches What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Reference ID: 3660954 48 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Taking Depakote or Depakene 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 each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can not swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene can cause serious side effects including: • Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose. • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. Reference ID: 3660954 49 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C). • Store Depakote Delayed Release Tablets below 86°F (30°C). • Store Depakote Sprinkle Capsules below 77°F (25°C). • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C). • Store Depakene Oral Solution below 86°F (30°C). Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Reference ID: 3660954 50 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depakote or Depakene 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 Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbvie.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote: Active ingredient: divalproex sodium Inactive ingredients: • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617 500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or AbbVie LTD, Barceloneta, PR 00617 Reference ID: 3660954 51 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For AbbVie Inc., North Chicago, IL 60064 U.S.A. Depakote Tablets: Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Oral Solution: Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. This Medication Guide has been approved by the U.S. Food and Drug Administration. 03-AXXX Month Year Reference ID: 3660954 52 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:55.245528	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018723s050lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 50}
11,304	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) tablets, for oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3, 5.4) • Pancreatitis, including fatal hemorrhagic cases (5.5) RECENT MAJOR CHANGES Warnings and Precautions, Birth Defects (5.2) 1/2015 Warnings and Precautions, Bleeding and Other Hematopoietic Disorders (5.8) 1/2015 Warnings and Precautions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions (5.12) 1/2015 INDICATIONS AND USAGE Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) DOSAGE AND ADMINISTRATION • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed (2.1, 2.2). • Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed (2.3). DOSAGE FORMS AND STRENGTHS Tablets: 125 mg, 250 mg and 500 mg (3) CONTRAINDICATIONS • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) (4, 5.1) • Suspected POLG-related disorder in children under two years of age (4, 5.1) • Known hypersensitivity to the drug (4, 5.12) • Urea cycle disorders (4, 5.6) • Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1) WARNINGS AND PRECAUTIONS • Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1) • Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4) • Pancreatitis; Depakote should ordinarily be discontinued (5.5) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.7) • Bleeding and other hematopoietic disorders; monitor platelet counts and coagulation tests (5.8) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.6, 5.9, 5.10) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.11) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction; discontinue Depakote (5.12) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14) ADVERSE REACTIONS • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3). • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3) USE IN SPECIFIC POPULATIONS • Pregnancy: Depakote can cause congenital malformations including neural tube defects and decreased IQ. (5.2, 5.3, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.14, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 1/2015 Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LIFE THREATENING ADVERSE REACTIONS 1 INDICATIONS AND USAGE 1.1 Mania 1.2 Epilepsy 1.3 Migraine 1.4 Important Limitations 2 DOSAGE AND ADMINISTRATION 2.1 Mania 2.2 Epilepsy 2.3 Migraine 2.4 General Dosing Advice 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Birth Defects 5.3 Decreased IQ Following in utero Exposure 5.4 Use in Women of Childbearing Potential 5.5 Pancreatitis 5.6 Urea Cycle Disorders 5.7 Suicidal Behavior and Ideation 5.8 Bleeding and Other Hematopoietic Disorders 5.9 Hyperammonemia 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use 5.11 Hypothermia 5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions 5.13 Interaction with Carbapenem Antibiotics 5.14 Somnolence in the Elderly 5.15 Monitoring: Drug Plasma Concentration 5.16 Effect on Ketone and Thyroid Function Tests 5.17 Effect on HIV and CMV Viruses Replication 5.18 Medication Residue in the Stool 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3683242 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 ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3, 5.4)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.5)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. 1.4 Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1), and Patient Counseling Information (17)]. Depakote is contraindicated for prophylaxis of migraine headaches in women who are pregnant. 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Simple and Complex Absence Seizures Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS • Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.12)]. • Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.6)]. • Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers- Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Birth Defects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.3 Decreased IQ Following in utero Exposure Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1)]. Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. 5.4 Use in Women of Childbearing Potential Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.5 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.6 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)]. 5.7 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 Depakote 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. 5.8 Bleeding and Other Hematopoietic Disorders Valproate is associated with dose-related thrombocytopenia. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Valproate use has also been associated with decreases in other cell lines and myelodysplasia. Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired von Willebrand’s disease), measurements of complete blood counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for blood counts and coagulation parameters prior to planned surgery and during pregnancy [see Use in Specific Populations (8.1)]. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. 5.9 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6, 5.10)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.6, 5.9)]. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.11 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking valproate. DRESS may be 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, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established. 5.13 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.14 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. 5.15 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.16 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.17 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 5.18 Medication Residue in the Stool There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Hepatic failure [see Warnings and Precautions (5.1)] • Birth defects [see Warnings and Precautions (5.2)] • Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)] • Pancreatitis [see Warnings and Precautions (5.5)] • Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)] • Suicidal behavior and ideation [see Warnings and Precautions (5.7)] • Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)] • Hypothermia [see Warnings and Precautions (5.11)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions (5.12)] Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Somnolence in the elderly [see Warnings and Precautions (5.14)] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Post-Marketing Experience The following adverse reactions have been identified during post approval use of Depakote. 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. Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens- Johnson syndrome. Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration. Neurologic: There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation. Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hematologic: Relative lymphocytosis, macrocytosis, leucopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Genitourinary: Enuresis and urinary tract infection. Special Senses: Hearing loss. Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following list provides information about the potential for an influence of valproate co administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11 epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Olanzapine No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine. Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions (5.2, 5.3)]. Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see Warnings and Precautions (5.3)]. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. An observational study has suggested that exposure to valproate products during pregnancy may increase the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. • Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: • Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). • Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. • Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. • To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. • Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see Warnings and Precautions (5.8)]. If valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal in the mother, then these parameters should also be monitored in the neonate. • Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. • Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. These data show up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other antiepileptic drugs taken in monotherapy. The major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and malformations of varying severity involving other body systems. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Juvenile Animal Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Divalproex sodium occurs as a white powder with a characteristic odor. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4) and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. Figure 1 Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda p < 0.05 PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Figure 2 The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following Table presents the findings for all patients randomized who had at least one post- randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty- seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Figure 4 Mean 4-week Migraine Rates Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 15 REFERENCES 1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Unit Dose Packages of 100.................………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Unit Dose Packages of 100................………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Unit Dose Packages of 100................……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.5)]. Birth Defects and Decreased IQ Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)]. Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant. Encourage patients 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 Use in Specific Populations (8.1)]. Suicidal Thinking and Behavior Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Counsel patients, their caregivers, and families that AEDs, including Depakote, 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. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.7)]. Hyperammonemia Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)]. CNS Depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. Multiorgan Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.12)]. Medication Residue in the Stool Instruct patients to notify their healthcare provider if they notice a medication residue in the stool [see Warnings and Precautions (5.18)]. Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium delayed release capsules) Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sprinkle Capsules DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: ◦ nausea or vomiting that does not go away ◦ loss of appetite ◦ pain on the right side of your stomach (abdomen) ◦ dark urine ◦ swelling of your face ◦ yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. 2. Depakote or Depakene may harm your unborn baby. ◦ If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects that affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects that affect the structures of the heart, head, arms, legs, and the opening where the urine comes out (urethra) on the bottom of the penis can also happen. ◦ Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. ◦ Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. ◦ If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. ◦ There may be other medicines to treat your condition that have a lower chance of causing birth defects and decreased IQ in your child. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ◦ Women who are pregnant must not take Depakote or Depakene to prevent migraine headaches. ◦ All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception). ◦ Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. ◦ Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: ◦ severe stomach pain that you may also feel in your back ◦ nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Stopping a seizure Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem called urea cycle disorder • are pregnant for the prevention of migraine headaches What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Taking Depakote or Depakene 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 each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you cannot swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene can cause serious side effects including: • Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your joints due to bleeding or bleeding from your mouth or nose. • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C). • Store Depakote Delayed Release Tablets below 86°F (30°C). • Store Depakote Sprinkle Capsules below 77°F (25°C). • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C). • Store Depakene Oral Solution below 86°F (30°C). Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene to other people, even if they have the same symptoms that you have. It may harm them. Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This Medication Guide summarizes the most important information about Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbvie.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote: Active ingredient: divalproex sodium Inactive ingredients: • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617 500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064 U.S.A. Depakote Tablets: Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Oral Solution: Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: January 2015 Reference ID: 3683242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:55.283534	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018723s051lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 51}
11,305	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) Tablets, for Oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3, 5.4) • Pancreatitis, including fatal hemorrhagic cases (5.5) ----------------------------INDICATIONS AND USAGE--------------------------- Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) -----------------------DOSAGE AND ADMINISTRATION---------------------- • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed (2.1, 2.2). • Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed (2.3). ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Tablets: 125 mg, 250 mg and 500 mg (3) ------------------------------CONTRAINDICATIONS------------------------------ • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) (4, 5.1) • Suspected POLG-related disorder in children under two years of age (4, 5.1) • Known hypersensitivity to the drug (4, 5.12) • Urea cycle disorders (4, 5.6) • Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1) ------------------------WARNINGS AND PRECAUTIONS---------------------- • Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1) • Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4) • Pancreatitis; Depakote should ordinarily be discontinued (5.5) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.7) • Thrombocytopenia; monitor platelet counts and coagulation tests (5.8) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.6, 5.9, 5.10) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.11) • Multi-organ hypersensitivity reaction; discontinue Depakote (5.12) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14) ------------------------------ADVERSE REACTIONS------------------------------ • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3). • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -------------------------------DRUG INTERACTIONS----------------------------- • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme- inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3) ------------------------USE IN SPECIFIC POPULATIONS---------------------- • Pregnancy: Depakote can cause congenital malformations including neural tube defects and decreased IQ. (5.2, 5.3, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.14, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 8/2014 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LIFE THREATENING ADVERSE REACTIONS 2.4 General Dosing Advice 1 INDICATIONS AND USAGE 3 DOSAGE FORMS AND STRENGTHS 1.1 Mania 4 CONTRAINDICATIONS 1.2 Epilepsy 5 WARNINGS AND PRECAUTIONS 1.3 Migraine 5.1 Hepatotoxicity 1.4 Important Limitations 5.2 Birth Defects 2 DOSAGE AND ADMINISTRATION 5.3 Decreased IQ Following in utero Exposure 2.1 Mania 5.4 Use in Women of Childbearing Potential 2.2 Epilepsy 5.5 Pancreatitis 2.3 Migraine 5.6 Urea Cycle Disorders Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.7 Suicidal Behavior and Ideation 5.8 Thrombocytopenia 5.9 Hyperammonemia 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use 5.11 Hypothermia 5.12 Multi-Organ Hypersensitivity Reactions 5.13 Interaction with Carbapenem Antibiotics 5.14 Somnolence in the Elderly 5.15 Monitoring: Drug Plasma Concentration 5.16 Effect on Ketone and Thyroid Function Tests 5.17 Effect on HIV and CMV Viruses Replication 5.18 Medication Residue in the Stool 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hepatotoxicity 17.2 Pancreatitis 17.3 Birth Defects and Decreased IQ 17.4 Suicidal Thinking and Behavior 17.5 Hyperammonemia 17.6 CNS Depression 17.7 Multi-Organ Hypersensitivity Reactions 17.8 Medication Residue in the Stool MEDICATION GUIDE Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 2 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 ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3, 5.4)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.5)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. 1.4 Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1), and Patient Counseling Information (17.3)]. Depakote is contraindicated for prophylaxis of migraine headaches in women who are pregnant. 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Simple and Complex Absence Seizures Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS • Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.12)]. • Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.6)]. • Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers- Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Birth Defects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.3 Decreased IQ Following in utero Exposure Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1)]. Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. 5.4 Use in Women of Childbearing Potential Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.5 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.6 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)]. 5.7 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 Depakote 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. 5.8 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. 5.9 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6, 5.10)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.6, 5.9)]. 5.11 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.12 Multi-Organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.13 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.14 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.15 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.16 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.17 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 5.18 Medication Residue in the Stool There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Post-Marketing Experience The following adverse reactions have been identified during post approval use of Depakote. 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. Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens- Johnson syndrome. Psychiatric: Emotional upset, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness. Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion. Genitourinary: Enuresis and urinary tract infection. Special Senses: Hearing loss. Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11 epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Olanzapine No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine. Oral Contraceptive Steroids Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions (5.2, 5.3)]. Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see Warnings and Precautions (5.3)]. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. An observational study has suggested that exposure to valproate products during pregnancy may increase the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. • Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: • Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). • Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. • Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. • To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. • Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Juvenile Animal Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 32 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 33 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4) and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 35 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 6. Study 1 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 28.8 + 0.2 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 36 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Depakote 15.7 - 3.2 1.8 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. Figure 1 p < 0.05 PBO = placebo, DVPX = Depakote Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 37 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Figure 2 Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 38 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post- randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 39 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 40 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty- seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Figure 4 Mean 4-week Migraine Rates Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 41 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 15 REFERENCES 1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Unit Dose Packages of 100.................………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 42 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Unit Dose Packages of 100................………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Unit Dose Packages of 100................……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide. 17.1 Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. 17.2 Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.5)]. 17.3 Birth Defects and Decreased IQ Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)]. Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant. Encourage patients 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 Use in Specific Populations (8.1)]. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 43 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17.4 Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including Depakote, 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. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.7)]. 17.5 Hyperammonemia Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)]. 17.6 CNS Depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. 17.7 Multi-Organ Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.12)]. 17.8 Medication Residue in the Stool Instruct patients to notify their healthcare provider if they notice a medication residue in the stool [see Warnings and Precautions (5.18)]. Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Tablets DEPAKOTE (dep-a-kOte) Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 44 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (divalproex sodium delayed release capsules) Sprinkle Capsules DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: o nausea or vomiting that does not go away o loss of appetite o pain on the right side of your stomach (abdomen) o dark urine o swelling of your face o yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. 2. Depakote or Depakene may harm your unborn baby. o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with Depakote or Depakene affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. o Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. o There may be other medicines to treat your condition that have a lower chance of causing birth defects and decreased IQ in your child. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 45 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda o Women who are pregnant must not take Depakote or Depakene to prevent migraine headaches. o All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception). o Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3. Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: o severe stomach pain that you may also feel in your back o nausea or vomiting that does not go away 4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: o thoughts about suicide or dying o attempts to commit suicide o new or worse depression o new or worse anxiety o feeling agitated or restless o panic attacks o trouble sleeping (insomnia) o new or worse irritability o acting aggressive, being angry, or violent o acting on dangerous impulses o an extreme increase in activity and talking (mania) o other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. o 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 46 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem called urea cycle disorder • are pregnant for the prevention of migraine headaches What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 47 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Taking Depakote or Depakene 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 each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can not swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene can cause serious side effects including: • Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose. • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 48 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C). • Store Depakote Delayed Release Tablets below 86°F (30°C). • Store Depakote Sprinkle Capsules below 77°F (25°C). • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C). • Store Depakene Oral Solution below 86°F (30°C). Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 49 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Depakote or Depakene 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 Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbvie.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote: Active ingredient: divalproex sodium Inactive ingredients: • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617 500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or AbbVie LTD, Barceloneta, PR 00617 Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 50 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For AbbVie Inc., North Chicago, IL 60064 U.S.A. Depakote Tablets: Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Oral Solution: Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. This Medication Guide has been approved by the U.S. Food and Drug Administration. 03-AXXX Month Year Reference ID: 3613509 dn2990v2-proposed-depakote tablets-autism-2014-jul-23 51 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:55.457396	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018723s053lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 53}
11,306	dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Depakote safely and effectively. See full prescribing information for Depakote. Depakote (divalproex sodium) tablets, for oral use Initial U.S. Approval: 1983 WARNINGS: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter (5.1) • Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3, 5.4) • Pancreatitis, including fatal hemorrhagic cases (5.5) RECENT MAJOR CHANGES Dosage and Administration, Dosing in Patients Taking Rufinamide (2.5) 2/2016 INDICATIONS AND USAGE Depakote is an anti-epileptic drug indicated for: • Treatment of manic episodes associated with bipolar disorder (1.1) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2) • Prophylaxis of migraine headaches (1.3) DOSAGE AND ADMINISTRATION • Depakote is administered orally in divided doses. Depakote should be swallowed whole and should not be crushed or chewed (2.1, 2.2). • Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2). • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed (2.3). DOSAGE FORMS AND STRENGTHS Tablets: 125 mg, 250 mg and 500 mg (3) CONTRAINDICATIONS • Hepatic disease or significant hepatic dysfunction (4, 5.1) • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) (4, 5.1) • Suspected POLG-related disorder in children under two years of age (4, 5.1) • Known hypersensitivity to the drug (4, 5.12) • Urea cycle disorders (4, 5.6) • Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1) WARNINGS AND PRECAUTIONS • Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1) • Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4) • Pancreatitis; Depakote should ordinarily be discontinued (5.5) • Suicidal behavior or ideation; Antiepileptic drugs, including Depakote, increase the risk of suicidal thoughts or behavior (5.7) • Bleeding and other hematopoietic disorders; monitor platelet counts and coagulation tests (5.8) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.6, 5.9, 5.10) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.11) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction; discontinue Depakote (5.12) • Somnolence in the elderly can occur. Depakote dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14) ADVERSE REACTIONS • Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3). • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1) • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2) • Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose (7.2) • Dosage adjustment of amitriptyline/nortriptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote (7.2) • Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3) USE IN SPECIFIC POPULATIONS • Pregnancy: Depakote can cause congenital malformations including neural tube defects and decreased IQ. (5.2, 5.3, 8.1) • Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4) • Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.14, 8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 2/2016 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LIFE THREATENING ADVERSE REACTIONS 1 INDICATIONS AND USAGE 1.1 Mania 1.2 Epilepsy 1.3 Migraine 1.4 Important Limitations 2 DOSAGE AND ADMINISTRATION Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 2 2.1 Mania 2.2 Epilepsy 2.3 Migraine 2.4 General Dosing Advice 2.5 Dosing in Patients Taking Rufinamide 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Birth Defects 5.3 Decreased IQ Following in utero Exposure 5.4 Use in Women of Childbearing Potential 5.5 Pancreatitis 5.6 Urea Cycle Disorders 5.7 Suicidal Behavior and Ideation 5.8 Bleeding and Other Hematopoietic Disorders 5.9 Hyperammonemia 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use 5.11 Hypothermia 5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions 5.13 Interaction with Carbapenem Antibiotics 5.14 Somnolence in the Elderly 5.15 Monitoring: Drug Plasma Concentration 5.16 Effect on Ketone and Thyroid Function Tests 5.17 Effect on HIV and CMV Viruses Replication 5.18 Medication Residue in the Stool 6 ADVERSE REACTIONS 6.1 Mania 6.2 Epilepsy 6.3 Migraine 6.4 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance 7.2 Effects of Valproate on Other Drugs 7.3 Topiramate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 14.1 Mania 14.2 Epilepsy 14.3 Migraine 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 3 FULL PRESCRIBING INFORMATION WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)]. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions (5.1)]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 4 is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2, 5.3, 5.4)]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.5)]. 1 INDICATIONS AND USAGE 1.1 Mania Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. 1.2 Epilepsy Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 5 1.3 Migraine Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. 1.4 Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1), and Patient Counseling Information (17)]. Depakote is contraindicated for prophylaxis of migraine headaches in women who are pregnant. 2 DOSAGE AND ADMINISTRATION Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. 2.1 Mania Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. 2.2 Epilepsy Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)]. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 6 Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. Simple and Complex Absence Seizures Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 7 The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)]. Antiepilepsy drugs should not be abruptly discontinued 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 epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. 2.3 Migraine Depakote is indicated for prophylaxis of migraine headaches in adults. Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. 2.4 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 8 Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 2.5 Dosing in Patients Taking Rufinamide Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose [see Drug Interactions (7.2)]. 3 DOSAGE FORMS AND STRENGTHS Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets 250 mg peach-colored tablets 500 mg lavender-colored tablets 4 CONTRAINDICATIONS • Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions (5.1)]. • Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.12)]. • Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.6)]. • Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 9 Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers- Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)]. 5.2 Birth Defects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 10 monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. 5.3 Decreased IQ Following in utero Exposure Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1)]. Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. 5.4 Use in Women of Childbearing Potential Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)]. To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 11 offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. 5.5 Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. 5.6 Urea Cycle Disorders Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)]. 5.7 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Depakote, 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 Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 12 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 Depakote 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. 5.8 Bleeding and Other Hematopoietic Disorders Valproate is associated with dose-related thrombocytopenia. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 13 remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Valproate use has also been associated with decreases in other cell lines and myelodysplasia. Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired von Willebrand’s disease), measurements of complete blood counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for blood counts and coagulation parameters prior to planned surgery and during pregnancy [see Use in Specific Populations (8.1)]. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. 5.9 Hyperammonemia Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6, 5.10)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.6, 5.9)]. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 14 5.11 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking valproate. DRESS may be 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, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established. 5.13 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)]. 5.14 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 15 discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)]. 5.15 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)]. 5.16 Effect on Ketone and Thyroid Function Tests Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. 5.17 Effect on HIV and CMV Viruses Replication There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 5.18 Medication Residue in the Stool There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Hepatic failure [see Warnings and Precautions (5.1)] • Birth defects [see Warnings and Precautions (5.2)] • Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)] • Pancreatitis [see Warnings and Precautions (5.5)] • Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)] • Suicidal behavior and ideation [see Warnings and Precautions (5.7)] • Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)] • Hypothermia [see Warnings and Precautions (5.11)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions (5.12)] Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 16 • Somnolence in the elderly [see Warnings and Precautions (5.14)] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse Reaction Depakote (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 17 Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. Respiratory System: Dyspnea, rhinitis. Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote- treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote- treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Depakote (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 18 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1 Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 19 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Body as a Whole: Back pain, chest pain, malaise. Cardiovascular System: Tachycardia, hypertension, palpitation. Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System: Petechia. Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 20 Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages: Rash, pruritus, dry skin. Special Senses: Taste perversion, abnormal vision, deafness, otitis media. Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.3 Migraine Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 Body System Reaction Depakote (N = 202) Placebo (N = 81) Gastrointestinal System Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1% Abdominal pain 9% 4% Increased appetite 6% 4% Nervous System Asthenia 20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight gain 8% 2% Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 21 Back pain 8% 6% Alopecia 7% 1% 1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis. The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever and malaise. Cardiovascular System: Vasodilatation. Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. Musculoskeletal System: Leg cramps and myalgia. Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Post-Marketing Experience The following adverse reactions have been identified during post approval use of Depakote. 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. Dermatologic: Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome. Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration. Neurologic: There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation. Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 22 Hematologic: Relative lymphocytosis, macrocytosis, leucopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Metabolism and nutrition: Weight gain. Reproductive: Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology. Genitourinary: Enuresis and urinary tract infection. Special Senses: Hearing loss. Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis. 7 DRUG INTERACTIONS 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 23 compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH- valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)]. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 24 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co- administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11- epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 25 lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Rufinamide Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. Rufinamide concentrations were increased by <16% to 70%, dependent on concentration of valproate (with the larger increases being seen in pediatric patients at high doses or concentrations of valproate). Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose [see Dosage and Administration (2.5)]. Similarly, patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults). Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 26 In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Clozapine In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Olanzapine No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine. Oral Contraceptive Steroids Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11)]. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 27 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions (5.2, 5.3)]. Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)]. Pregnancy Registry To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see Warnings and Precautions (5.3)]. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. An observational study has suggested that exposure to valproate products during pregnancy may increase the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits. Clinical Considerations • Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 28 estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). • Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. • Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: • Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). • Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. • Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. • To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. • Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see Warnings and Precautions (5.8)]. If valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal in the mother, then these parameters should also be monitored in the neonate. • Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. • Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. Data Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 29 Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. These data show up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other antiepileptic drugs taken in monotherapy. The major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and malformations of varying severity involving other body systems. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 30 8.3 Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. 8.4 Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Juvenile Animal Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 31 The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. 8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. 11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 32 Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. In addition, individual tablets contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40. 250 mg tablets: FD&C Yellow No. 6 and iron oxide. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). 12.2 Pharmacodynamics The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 33 which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)]. 12.3 Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 34 Distribution Protein Binding The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 35 ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)]. Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4) and Warnings and Precautions (5.1)]. Renal Disease A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 36 Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Impairment of Fertility Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm parameters and fertility in humans is unknown. 14 CLINICAL STUDIES 14.1 Mania The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 YMRS Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 28.8 + 0.2 Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 37 Depakote 28.5 - 9.5 9.7 BPRS-A Total Score Group Baseline1 BL to Wk 32 Difference3 Placebo 76.2 + 1.8 Depakote 76.4 -17.0 18.8 GAS Score Group Baseline1 BL to Wk 32 Difference3 Placebo 31.8 0.0 Depakote 30.3 + 18.1 18.1 1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation- carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 38.9 - 4.4 Lithium 37.9 -10.5 6.1 Depakote 38.1 - 9.5 5.1 MSS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 18.9 - 2.5 Lithium 18.5 - 6.2 3.7 Depakote 18.9 - 6.0 3.5 BIS Total Score Group Baseline1 BL to Day 212 Difference3 Placebo 16.4 - 1.4 Lithium 16.0 - 3.8 2.4 Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 38 Depakote 15.7 - 3.2 1.8 1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and placebo and lithium and placebo Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. Figure 1 p < 0.05 PBO = placebo, DVPX = Depakote 14.2 Epilepsy The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 39 concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence Depakote 75 16.0 8.9* Placebo 69 14.5 11.5 * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Figure 2 Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 40 The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post- randomization assessment. Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks Treatment Number of Patients Baseline Incidence Randomized Phase Incidence High dose Depakote 131 13.2 10.7* Low dose Depakote 134 14.2 13.8 * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. Figure 3 Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 41 14.3 Migraine The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 42 The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty- seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. Figure 4 Mean 4-week Migraine Rates Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 43 1 Mean dose of Depakote was 1,087 mg/day. 2 Dose of Depakote was 500 or 1,000 mg/day. 15 REFERENCES 1.Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252. 16 HOW SUPPLIED/STORAGE AND HANDLING Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: Bottles of 100………………………………………..(NDC 0074-6212-13) Unit Dose Packages of 100.................………………(NDC 0074-6212-11) 250 mg peach-colored tablets: Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 44 Bottles of 100……………………………………….(NDC 0074-6214-13) Bottles of 500……………………………………….(NDC 0074-6214-53) Unit Dose Packages of 100................………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Unit Dose Packages of 100................……………...(NDC 0074-6215-11) Recommended storage Store tablets below 86°F (30°C). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)]. Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.5)]. Birth Defects and Decreased IQ Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)]. Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant. Encourage patients 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 Use in Specific Populations (8.1)]. Suicidal Thinking and Behavior Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 45 Counsel patients, their caregivers, and families that AEDs, including Depakote, 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. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.7)]. Hyperammonemia Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)]. CNS Depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. Multiorgan Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.12)]. Medication Residue in the Stool Instruct patients to notify their healthcare provider if they notice a medication residue in the stool [see Warnings and Precautions (5.18)]. Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. MEDICATION GUIDE DEPAKOTE ER (dep-a-kOte) (divalproex sodium) Extended Release Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium) Tablets DEPAKOTE (dep-a-kOte) (divalproex sodium delayed release capsules) Sprinkle Capsules Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 46 DEPAKENE (dep-a-keen) (valproic acid) Capsules and Oral Solution Read this Medication Guide before you start taking Depakote or Depakene 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 Depakote or Depakene? Do not stop Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. Depakote and Depakene can cause serious side effects, including: 1.Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: ◦nausea or vomiting that does not go away ◦loss of appetite ◦pain on the right side of your stomach (abdomen) ◦dark urine ◦swelling of your face ◦yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug. 2.Depakote or Depakene may harm your unborn baby. ◦If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at risk for serious birth defects that affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects that affect the structures of the heart, head, arms, legs, and the opening where the urine comes out (urethra) on the bottom of the penis can also happen. ◦Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors. ◦Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect. ◦If you take Depakote or Depakene during pregnancy for any medical condition, your child is at risk for having a lower IQ. ◦There may be other medicines to treat your condition that have a lower chance of causing birth defects and decreased IQ in your child. ◦Women who are pregnant must not take Depakote or Depakene to prevent migraine headaches. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 47 ◦All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Depakote or Depakene. If the decision is made to use Depakote or Depakene, you should use effective birth control (contraception). ◦Tell your healthcare provider right away if you become pregnant while taking Depakote or Depakene. You and your healthcare provider should decide if you will continue to take Depakote or Depakene while you are pregnant. ◦Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 3.Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: ◦severe stomach pain that you may also feel in your back ◦nausea or vomiting that does not go away 4.Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a 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 Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or Depakene 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). Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 48 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 are Depakote and Depakene? Depakote and Depakene come in different dosage forms with different usages. Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used: • to treat manic episodes associated with bipolar disorder • alone or with other medicines to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types • to prevent migraine headaches Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or with other medicines, to treat: • complex partial seizures in adults and children 10 years of age and older • simple and complex absence seizures, with or without other seizure types Who should not take Depakote or Depakene? Do not take Depakote or Depakene if you: • have liver problems • have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and Depakene. • have a genetic problem called urea cycle disorder • are pregnant for the prevention of migraine headaches What should I tell my healthcare provider before taking Depakote or Depakene? Before you take Depakote or Depakene, tell your healthcare provider if you: • have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome) • drink alcohol • are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depakote or Depakene. • have or have had depression, mood problems, or suicidal thoughts or behavior • have any other medical conditions Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 49 Taking Depakote or Depakene 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 each time you get a new medicine. How should I take Depakote or Depakene? • Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote or Depakene to take and when to take it. • Your healthcare provider may change your dose. • Do not change your dose of Depakote or Depakene without talking to your healthcare provider. • Do not stop taking Depakote or Depakene without first talking to your healthcare provider. Stopping Depakote or Depakene suddenly can cause serious problems. • Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you cannot swallow Depakote or Depakene whole. You may need a different medicine. • Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules. • If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Depakote or Depakene? • Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affects you. Depakote and Depakene can slow your thinking and motor skills. What are the possible side effects with Depakote or Depakene? • See “What is the most important information I should know about Depakote or Depakene?” Depakote or Depakene can cause serious side effects including: • Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your joints due to bleeding or bleeding from your mouth or nose. • High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. • Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma. • Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 50 • Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of Depakote or Depakene. Call your healthcare provider right away, if you have any of the symptoms listed above. The common side effects of Depakote and Depakene include: • nausea • headache • sleepiness • vomiting • weakness • tremor • dizziness • stomach pain • blurry vision • double vision • diarrhea • increased appetite • weight gain • hair loss • loss of appetite • problems with walking or coordination These are not all of the possible side effects of Depakote or Depakene. 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 Depakote or Depakene? • Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C). • Store Depakote Delayed Release Tablets below 86°F (30°C). • Store Depakote Sprinkle Capsules below 77°F (25°C). • Store Depakene Capsules between 59°F to 77°F (15°C to 25°C). • Store Depakene Oral Solution below 86°F (30°C). Keep Depakote or Depakene and all medicines out of the reach of children. General information about the safe and effective use of Depakote or Depakene Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene to other people, even if they have the same symptoms that you have. It may harm them. Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 51 This Medication Guide summarizes the most important information about Depakote or Depakene. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Depakote or Depakene that is written for health professionals. For more information, go to www.rxabbvie.com or call 1-800-633-9110. What are the ingredients in Depakote or Depakene? Depakote: Active ingredient: divalproex sodium Inactive ingredients: • Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. • Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin. Individual tablets also contain: 125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40, 250 mg tablets: FD&C Yellow No. 6 and iron oxide, 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. • Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate. Depakene: Active ingredient: valproic acid Inactive ingredients: • Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben, and titanium dioxide. • Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and natural and artificial flavors. Depakote ER: 250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617 500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064 U.S.A. Depakote Tablets: Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dn3344v4-proposed-depakote-tab-obesity-nail-ddis-2016-feb-17 52 Mfd. by AbbVie LTD, Barceloneta, PR 00617 For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakote Sprinkle Capsules: AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Capsules: Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. Depakene Oral Solution: Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A. OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A. For AbbVie Inc., North Chicago, IL 60064, U.S.A. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: February 2016 03-B303 Reference ID: 3888904 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:55.684532	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018723s056lbl.pdf', 'application_number': 18723, 'submission_type': 'SUPPL ', 'submission_number': 56}
11,307	1 Bristol-Myers Squibb Company BuSpar® (buspirone HCl, USP) (Patient Instruction Sheet Included) DESCRIPTION BuSpar® (buspirone hydrochloride, USP) is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs. Buspirone hydrochloride is a white crystalline, water soluble compound with a molecular weight of 422.0. Chemically, buspirone hydrochloride is 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8- azaspiro[4.5]decane-7,9- dione monohydrochloride. The empirical formula C21H31N502 · HCl is represented by the following structural formula: BuSpar is supplied as tablets for oral administration containing 5 mg, 10 mg, 15 mg, or 30 mg of buspirone hydrochloride, USP (equivalent to 4.6 mg, 9.1 mg,13.7, and 27.4 mg of buspirone free base respectively). The 5-mg and 10-mg tablets are scored so they can be bisected. Thus, the 5-mg tablet can also provide a 2.5-mg dose, and the 10-mg tablet can provide a 5-mg dose. The 15-mg and 30-mg tablets are provided in the DIVIDOSE® tablet design. These tablets are scored so they can be either bisected or trisected. Thus, a single 15-mg tablet can provide the following doses: 15 mg (entire tablet), 10 mg (two thirds of a tablet), 7.5 mg (one half of a tablet), or 5 mg (one third of a tablet). A single 30-mg tablet can provide the following doses: 30 mg (entire tablet), 20 mg (two thirds of a tablet), 15 mg (one half of a tablet), or 10 mg (one third of a tablet). BuSpar Tablets contain the following inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 30-mg tablet also contains iron oxide. CLINICAL PHARMACOLOGY The mechanism of action of buspirone is unknown. Buspirone differs from typical benzodiazepine anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent sedative effect that is associated with more typical anxiolytics. In vitro preclinical studies have shown that buspirone has a high affinity for serotonin (5-HT1A) receptors. Buspirone has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models. Rx only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmitter systems. BuSpar is rapidly absorbed in man and undergoes extensive first-pass metabolism. In a radiolabeled study, unchanged buspirone in the plasma accounted for only about 1% of the radioactivity in the plasma. Following oral administration, plasma concentrations of unchanged buspirone are very low and variable between subjects. Peak plasma levels of 1 to 6 ng/mL have been observed 40 to 90 minutes after single oral doses of 20 mg. The single-dose bioavailability of unchanged buspirone when taken as a tablet is on the average about 90% of an equivalent dose of solution, but there is large variability. The effects of food upon the bioavailability of BuSpar have been studied in eight subjects. They were given a 20-mg dose with and without food; the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of unchanged buspirone increased by 84% and 116% respectively, but the total amount of buspirone immunoreactive material did not change. This suggests that food may decrease the extent of presystemic clearance of buspirone. A multiple-dose study conducted in 15 subjects suggests that buspirone has nonlinear pharmacokinetics. Thus, dose increases and repeated dosing may lead to somewhat higher blood levels of unchanged buspirone than would be predicted from results of single-dose studies. An in vitro protein binding study indicated that approximately 86% of buspirone is bound to plasma proteins. It was also observed that aspirin increased the plasma levels of free buspirone by 23%, while flurazepam decreased the plasma levels of free buspirone by 20%. However, it is not known whether these drugs cause similar effects on plasma levels of free buspirone in vivo, or whether such changes, if they do occur, cause clinically significant differences in treatment outcome. An in vitro study indicated that buspirone did not displace highly protein-bound drugs such as phenytoin, warfarin, and propranolol from plasma protein, and that buspirone may displace digoxin. Buspirone is metabolized primarily by oxidation, which in vitro has been shown to be mediated by cytochrome P450 3A4 (CYP3A4). (See PRECAUTIONS, Drug Interactions section.) Several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP), are produced. In animal models predictive of anxiolytic potential, 1-PP has about one quarter of the activity of buspirone, but is present in up to 20-fold greater amounts. However, this is probably not important in humans: blood samples from humans chronically exposed to BuSpar (buspirone hydrochloride) do not exhibit high levels of 1-PP; mean values are approximately 3 ng/mL and the highest human blood level recorded among 108 chronically dosed patients was 17 ng/mL, less than 1/200th of 1-PP levels found in animals given large doses of buspirone without signs of toxicity. In a single-dose study using 14C-labeled buspirone, 29% to 63% of the dose was excreted in the urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose. The average elimination half-life of unchanged buspirone after single doses of 10 to 40 mg is about 2 to 3 hours. Special Populations Age and Gender Effects After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC and Cmax) were observed between elderly and younger subjects or between men and women. Hepatic Impairment After multiple-dose administration of buspirone to patients with hepatic impairment, steady-state AUC of buspirone increased 13-fold compared with healthy subjects (see PRECAUTIONS section). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal Impairment After multiple-dose administration of buspirone to renally impaired (Clcr = 10-70 mL/min/1.73 m2) patients, steady-state AUC of buspirone increased 4-fold compared with healthy (Clcr ≥ 80 mL/min/1.73 m2) subjects (see PRECAUTIONS section). Race Effects The effects of race on the pharmacokinetics of buspirone have not been studied. INDICATIONS AND USAGE BuSpar is indicated for the management of anxiety disorders or 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. The efficacy of BuSpar has been demonstrated in controlled clinical trials of outpatients whose diagnosis roughly corresponds to Generalized Anxiety Disorder (GAD). Many of the patients enrolled in these studies also had coexisting depressive symptoms and BuSpar relieved anxiety in the presence of these coexisting depressive symptoms. The patients evaluated in these studies had experienced symptoms for periods of 1 month to over 1 year prior to the study, with an average symptom duration of 6 months. Generalized Anxiety Disorder (300.02) is described in the American Psychiatric Association's Diagnostic and Statistical Manual, III1 as follows: Generalized, persistent anxiety (of at least 1 month continual duration), manifested by symptoms from three of the four following categories: 1. Motor tension: shakiness, jitteriness, jumpiness, trembling, tension, muscle aches, fatigability, inability to relax, eyelid twitch, furrowed brow, strained face, fidgeting, restlessness, easy startle. 2. Autonomic hyperactivity: sweating, heart pounding or racing, cold, clammy hands, dry mouth, dizziness, lightheadedness, paresthesias (tingling in hands or feet), upset stomach, hot or cold spells, frequent urination, diarrhea, discomfort in the pit of the stomach, lump in the throat, flushing, pallor, high resting pulse and respiration rate. 3. Apprehensive expectation: anxiety, worry, fear, rumination, and anticipation of misfortune to self or others. 4. Vigilance and scanning: hyperattentiveness resulting in distractibility, difficulty in concentrating, insomnia, feeling "on edge," irritability, impatience. The above symptoms would not be due to another mental disorder, such as a depressive disorder or schizophrenia. However, mild depressive symptoms are common in GAD. The effectiveness of BuSpar in long-term use, that is, for more than 3 to 4 weeks, has not been demonstrated in controlled trials. There is no body of evidence available that systematically addresses the appropriate duration of treatment for GAD. However, in a study of long-term use, 264 patients were treated with BuSpar for 1 year without ill effect. Therefore, the physician who elects to use BuSpar for extended periods should periodically reassess the usefulness of the drug for the individual patient. CONTRAINDICATIONS BuSpar is contraindicated in patients hypersensitive to buspirone hydrochloride. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS The administration of BuSpar to a patient taking a monoamine oxidase inhibitor (MAOI) may pose a hazard. There have been reports of the occurrence of elevated blood pressure when BuSpar (buspirone hydrochloride) has been added to a regimen including an MAOI. Therefore, it is recommended that BuSpar not be used concomitantly with an MAOI. Because BuSpar has no established antipsychotic activity, it should not be employed in lieu of appropriate antipsychotic treatment. PRECAUTIONS General Interference with Cognitive and Motor Performance Studies indicate that BuSpar is less sedating than other anxiolytics and that it does not produce significant functional impairment. However, its CNS effects in any individual patient may not be predictable. Therefore, patients should be cautioned about operating an automobile or using complex machinery until they are reasonably certain that buspirone treatment does not affect them adversely. While formal studies of the interaction of BuSpar (buspirone hydrochloride) with alcohol indicate that buspirone does not increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid concomitant use of alcohol and buspirone. Potential for Withdrawal Reactions in Sedative/Hypnotic/Anxiolytic Drug-Dependent Patients Because BuSpar does not exhibit cross-tolerance with benzodiazepines and other common sedative/hypnotic drugs, it will not block the withdrawal syndrome often seen with cessation of therapy with these drugs. Therefore, before starting therapy with BuSpar, it is advisable to withdraw patients gradually, especially patients who have been using a CNS-depressant drug chronically, from their prior treatment. Rebound or withdrawal symptoms may occur over varying time periods, depending in part on the type of drug, and its effective half-life of elimination. The syndrome of withdrawal from sedative/hypnotic/anxiolytic drugs can appear as any combination of irritability, anxiety, agitation, insomnia, tremor, abdominal cramps, muscle cramps, vomiting, sweating, flu-like symptoms without fever, and occasionally, even as seizures. Possible Concerns Related to Buspirone's Binding to Dopamine Receptors Because buspirone can bind to central dopamine receptors, a question has been raised about its potential to cause acute and chronic changes in dopamine-mediated neurological function (eg, dystonia, pseudo- parkinsonism, akathisia, and tardive dyskinesia). Clinical experience in controlled trials has failed to identify any significant neuroleptic-like activity; however, a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone-treated patients. The syndrome may be explained in several ways. For example, buspirone may increase central noradrenergic activity; alternatively, the effect may be attributable to dopaminergic effects (ie, represent akathisia). Obviously, the question cannot be totally resolved at this point in time. Generally, long-term sequelae of any drug's use can be identified only after several years of marketing. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Patients To assure safe and effective use of BuSpar, the following information and instructions should be given to patients: 1. Inform your physician about any medications, prescription or non-prescription, alcohol, or drugs that you are now taking or plan to take during your treatment with BuSpar. 2. Inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking BuSpar. 3. Inform your physician if you are breast-feeding an infant. 4. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery. 5. You should take BuSpar consistently, either always with or always without food. 6. During your treatment with BuSpar, avoid drinking large amounts of grapefruit juice. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions Psychotropic Agents MAO inhibitors: It is recommended that BuSpar (buspirone hydrochloride) not be used concomitantly with MAO inhibitors (see WARNINGS section). Amitriptyline: After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) of amitriptyline or its metabolite nortriptyline were observed. Diazepam: After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed. Haloperidol: In a study in normal volunteers, concomitant administration of buspirone and haloperidol resulted in increased serum haloperidol concentrations. The clinical significance of this finding is not clear. Nefazodone: [see Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4)] Trazodone: There is one report suggesting that the concomitant use of Desyrel® (trazodone hydrochloride) and buspirone may have caused 3- to 6-fold elevations on SGPT (ALT) in a few patients. In a similar study attempting to replicate this finding, no interactive effect on hepatic transaminases was identified. Triazolam/Flurazepam: Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine. Other Psychotropics: Because the effects of concomitant administration of buspirone with most other psychotropic drugs have not been studied, the concomitant use of buspirone with other CNS-active drugs should be approached with caution. Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4) Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and the following: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diltiazem and Verapamil: In a study of nine healthy volunteers, coadministration of buspirone (10 mg as a single dose) with verapamil (80 mg t.i.d.) or diltiazem (60 mg t.i.d.) increased plasma buspirone concentrations (verapamil increased AUC and Cmax of buspirone 3.4-fold while diltiazem increased AUC and Cmax 5.3-fold and 4-fold, respectively.) Adverse events attributable to buspirone may be more likely during concomitant administration with either diltiazem or verapamil. Subsequent dose adjustment may be necessary and should be based on clinical assessment. Erythromycin: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5-fold increase in Cmax and 6-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg b.i.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Grapefruit Juice: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with grapefruit juice (200 mL double-strength t.i.d. for 2 days) increased plasma buspirone concentrations (4.3-fold increase in Cmax; 9.2-fold increase in AUC). Patients receiving buspirone should be advised to avoid drinking such large amounts of grapefruit juice. Itraconazole: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13-fold increase in Cmax and 19-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg q.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Nefazodone: In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg b.i.d.) with nefazodone (250 mg b.i.d.) resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in Cmax and up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP. With 5-mg b.i.d. doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and meta-chlorophenylpiperazine (9%). Slight increases in Cmax were observed for nefazodone (8%) and its metabolite HO-NEF (11%). Rifampin: In a study in healthy volunteers, coadministration of buspirone (30 mg as a single dose) with rifampin (600 mg/day for 5 days) decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. If the two drugs are to be used in combination, the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other Inhibitors and Inducers of CYP3A4: Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone, or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other Drugs Cimetidine: Coadministration of buspirone with cimetidine was found to increase Cmax (40%) and Tmax (2–fold), but had minimal effects on the AUC of buspirone. Protein Binding In vitro, buspirone does not displace tightly bound drugs like phenytoin, propranolol, and warfarin from serum proteins. However, there has been one report of prolonged prothrombin time when buspirone was added to the regimen of a patient treated with warfarin. The patient was also chronically receiving phenytoin, phenobarbital, digoxin, and Synthroid® . In vitro, buspirone may displace less firmly bound drugs like digoxin. The clinical significance of this property is unknown. Therapeutic levels of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol, thioridazine, and tolbutamide had only a limited effect on the extent of binding of buspirone to plasma proteins (see CLINICAL PHARMACOLOGY section). Drug/Laboratory Test Interactions Buspirone is not known to interfere with commonly employed clinical laboratory tests. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed in rats during a 24-month study at approximately 133 times the maximum recommended human oral dose; or in mice, during an 18-month study at approximately 167 times the maximum recommended human oral dose. With or without metabolic activation, buspirone did not induce point mutations in five strains of Salmonella typhimurium (Ames Test) or mouse lymphoma L5178YTK+ cell cultures, nor was DNA damage observed with buspirone in Wi-38 human cells. Chromosomal aberrations or abnormalities did not occur in bone marrow cells of mice given one or five daily doses of buspirone. Pregnancy: Teratogenic Effects Pregnancy Category B: No fertility impairment or fetal damage was observed in reproduction studies performed in rats and rabbits at buspirone doses of approximately 30 times the maximum recommended human dose. In humans, however, adequate and well-controlled studies during pregnancy have not been performed. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery The effect of BuSpar on labor and delivery in women is unknown. No adverse effects were noted in reproduction studies in rats. Nursing Mothers The extent of the excretion in human milk of buspirone or its metabolites is not known. In rats, however, buspirone and its metabolites are excreted in milk. BuSpar administration to nursing women should be avoided if clinically possible. Pediatric Use The safety and effectiveness of BuSpar (buspirone hydrochloride) have not been determined in individuals below 18 years of age. Synthroid® is the registered trademark of Knoll Pharmaceutical Company. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use In one study of 6632 patients who received Buspar for the treatment of anxiety, 605 patients were ≥ 65 years old and 41 were ≥ 75 years old; the safety and efficacy profiles for these 605 elderly patients (mean age =70.8 years) were similar to those in the younger population (mean age = 43.3 years). The review of other spontaneously reported adverse clinical events has not identified differences in reporting between elderly and younger patients, but greater sensitivity of some older patients can not be ruled out. Use in Patients With Impaired Hepatic or Renal Function Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of BuSpar to patients with severe hepatic or renal impairment cannot be recommended (see CLINICAL PHARMACOLOGY section). ADVERSE REACTIONS (See also PRECAUTIONS) Commonly Observed The more commonly observed untoward events associated with the use of BuSpar not seen at an equivalent incidence among placebo-treated patients include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Associated with Discontinuation of Treatment One guide to the relative clinical importance of adverse events associated with BuSpar is provided by the frequency with which they caused drug discontinuation during clinical testing. Approximately 10% of the 2200 anxious patients who participated in the BuSpar premarketing clinical efficacy trials in anxiety disorders lasting 3 to 4 weeks discontinued treatment due to an adverse event. The more common events causing discontinuation included: central nervous system disturbances (3.4%), primarily dizziness, insomnia, nervousness, drowsiness, and lightheaded feeling; gastrointestinal disturbances (1.2%), primarily nausea; and miscellaneous disturbances (1.1%), primarily headache and fatigue. In addition, 3.4% of patients had multiple complaints, none of which could be characterized as primary. Incidence in Controlled Clinical Trials The table that follows enumerates adverse events that occurred at a frequency of 1% or more among BuSpar (buspirone hydrochloride) patients who participated in 4-week, controlled trials comparing BuSpar with placebo. The frequencies were obtained from pooled data for 17 trials. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. Comparison of the cited figures, however, does provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS* (Percent of Patients Reporting) Adverse Experience BuSpar (n=477) Placebo (n=464) Cardiovascular Tachycardia/Palpitations 1 1 CNS Dizziness 12 3 Drowsiness 10 9 Nervousness 5 1 Insomnia 3 3 Lightheadedness 3 — Decreased Concentration 2 2 Excitement 2 — Anger/Hostility 2 — Confusion 2 — Depression 2 2 EENT Blurred Vision 2 — Gastrointestinal Nausea 8 5 Dry Mouth 3 4 Abdominal/Gastric Distress 2 2 Diarrhea 2 — Constipation 1 2 Vomiting 1 2 Musculoskeletal Musculoskeletal Aches/Pains 1 — Neurological Numbness 2 — Paresthesia 1 — Incoordination 1 — Tremor 1 — Skin Skin Rash 1 — Miscellaneous Headache 6 3 Fatigue 4 4 Weakness 2 — Sweating/Clamminess 1 — * Events reported by at least 1% of BuSpar patients are included. —Incidence less than 1%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other Events Observed During the Entire Premarketing Evaluation of BuSpar During its premarketing assessment, BuSpar was evaluated in over 3500 subjects. This section reports event frequencies for adverse events occurring in approximately 3000 subjects from this group who took multiple doses of BuSpar in the dose range for which BuSpar is being recommended (ie, the modal daily dose of BuSpar fell between 10 and 30 mg for 70% of the patients studied) and for whom safety data were systematically collected. The conditions and duration of exposure to BuSpar varied greatly, involving well- controlled studies as well as experience in open and uncontrolled clinical settings. As part of the total experience gained in clinical studies, various adverse events were reported. In the absence of appropriate controls in some of the studies, a causal relationship to BuSpar (buspirone hydrochloride) treatment cannot be determined. The list includes all undesirable events reasonably associated with the use of the drug. The following enumeration by organ system describes events in terms of their relative frequency of reporting in this data base. Events of major clinical importance are also described in the PRECAUTIONS section. The following definitions of frequency are used: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare events are those occurring in less than 1/1000 patients. Cardiovascular Frequent was nonspecific chest pain; infrequent were syncope, hypotension, and hypertension; rare were cerebrovascular accident, congestive heart failure, myocardial infarction, cardiomyopathy, and bradycardia. Central Nervous System Frequent were dream disturbances; infrequent were depersonalization, dysphoria, noise intolerance, euphoria, akathisia, fearfulness, loss of interest, dissociative reaction, hallucinations, involuntary movements, slowed reaction time, suicidal ideation, and seizures; rare were feelings of claustrophobia, cold intolerance, stupor, and slurred speech and psychosis. EENT Frequent were tinnitus, sore throat, and nasal congestion; infrequent were redness and itching of the eyes, altered taste, altered smell, and conjunctivitis; rare were inner ear abnormality, eye pain, photophobia, and pressure on eyes. Endocrine Rare were galactorrhea and thyroid abnormality. Gastrointestinal Infrequent were flatulence, anorexia, increased appetite, salivation, irritable colon, and rectal bleeding; rare was burning of the tongue. Genitourinary Infrequent were urinary frequency, urinary hesitancy, menstrual irregularity and spotting, and dysuria; rare were amenorrhea, pelvic inflammatory disease, enuresis, and nocturia. Musculoskeletal Infrequent were muscle cramps, muscle spasms, rigid/stiff muscles, and arthralgias; rare was muscle weakness. Respiratory Infrequent were hyperventilation, shortness of breath, and chest congestion; rare was epistaxis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sexual Function Infrequent were decreased or increased libido; rare were delayed ejaculation and impotence. Skin Infrequent were edema, pruritus, flushing, easy bruising, hair loss, dry skin, facial edema, and blisters; rare were acne and thinning of nails. Clinical Laboratory Infrequent were increases in hepatic aminotransferases (SGOT, SGPT); rare were eosinophilia, leukopenia, and thrombocytopenia. Miscellaneous Infrequent were weight gain, fever, roaring sensation in the head, weight loss, and malaise; rare were alcohol abuse, bleeding disturbance, loss of voice, and hiccoughs. POSTINTRODUCTION CLINICAL EXPERIENCE Postmarketing experience has shown an adverse experience profile similar to that given above. Voluntary reports since introduction have included rare occurrences of allergic reactions (including urticaria), angioedema, cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions, ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional lability, serotonin syndrome, transient difficulty with recall, urinary retention, and visual changes (including tunnel vision). Because of the uncontrolled nature of these spontaneous reports, a causal relationship to BuSpar treatment has not been determined. DRUG ABUSE AND DEPENDENCE Controlled Substance Class BuSpar (buspirone hydrochloride) is not a controlled substance. Physical and Psychological Dependence In human and animal studies, buspirone has shown no potential for abuse or diversion and there is no evidence that it causes tolerance, or either physical or psychological dependence. Human volunteers with a history of recreational drug or alcohol usage were studied in two double-blind clinical investigations. None of the subjects were able to distinguish between BuSpar and placebo. By contrast, subjects showed a statistically significant preference for methaqualone and diazepam. Studies in monkeys, mice, and rats have indicated that buspirone lacks potential for abuse. Following chronic administration in the rat, abrupt withdrawal of buspirone did not result in the loss of body weight commonly observed with substances that cause physical dependency. Although there is no direct evidence that BuSpar causes physical dependence or drug-seeking behavior, it is difficult to predict from experiments the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of BuSpar misuse or abuse (eg, development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Signs and Symptoms In clinical pharmacology trials, doses as high as 375 mg/day were administered to healthy male volunteers. As this dose was approached, the following symptoms were observed: nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. A few cases of overdosage have been reported, with complete This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda recovery as the usual outcome. No deaths have been reported following overdosage with BuSpar alone. Rare cases of intentional overdosage with a fatal outcome were invariably associated with ingestion of multiple drugs and/or alcohol, and a causal relationship to buspirone could not be determined. Toxicology studies of buspirone yielded the following LD50 values: mice, 655 mg/kg; rats, 196 mg/kg; dogs, 586 mg/kg; and monkeys, 356 mg/kg. These dosages are 160 to 550 times the recommended human daily dose. Recommended Overdose Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage. Respiration, pulse, and blood pressure should be monitored as in all cases of drug overdosage. No specific antidote is known to buspirone, and dialyzability of buspirone has not been determined. DOSAGE AND ADMINISTRATION The recommended initial dose is 15 mg daily (7.5 mg b.i.d.). To achieve an optimal therapeutic response, at intervals of 2 to 3 days the dosage may be increased 5 mg per day, as needed. The maximum daily dosage should not exceed 60 mg per day. In clinical trials allowing dose titration, divided doses of 20 to 30 mg per day were commonly employed. The bioavailability of buspirone is increased when given with food as compared to the fasted state (see CLINICAL PHARMACOLOGY section). Consequently, patients should take buspirone in a consistent manner with regard to the timing of dosing; either always with or always without food. When buspirone is to be given with a potent inhibitor of CYP3A4 the dosage recommendations described in the PRECAUTIONS: Drug Interactions section should be followed. HOW SUPPLIED BuSpar® (buspirone hydrochloride tablets, USP) Tablets, 5 mg and 10 mg (white, ovoid-rectangular with score, MJ logo, strength and the name BuSpar embossed) are available in bottles of 100 and 500, and in cartons containing 100 individually packaged tablets. 5-mg tablets NDC 0087-0818-41 Bottles of 100 NDC 0087-0818-44 Bottles of 500 NDC 0087-0818-43 Cartons of 100 unit dose 10-mg tablets NDC 0087-0819-41 Bottles of 100 NDC 0087-0819-44 Bottles of 500 Tablets, 15 mg white, in the DIVIDOSE® tablet design imprinted with the MJ logo, are available in bottles of 60 and 180. Tablets, 30 mg pink, in the DIVIDOSE® tablet design imprinted with the MJ logo, are available in bottles of 60. The 15-mg and 30-mg tablets are scored so that they can be either bisected or trisected. The 15-mg tablet has ID number 822 on one side and on the reverse side, the number 5 on each trisect segment. The 30-mg tablet has ID number 824 on one side and on the reverse side, the number 10 on each trisect segment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15-mg tablets NDC 0087-0822-32 Bottles of 60 NDC 0087-0822-33 Bottles of 180 30-mg tablets NDC 0087-0824-81 Bottles of 60 U.S. Patent Nos. 5,015,646 and 6,008,222 Store at Room Temperature−Protect from temperatures greater than 86° F (30° C). Dispense in a tight, light-resistant container (USP). REFERENCE 1. American Psychiatric Association, Ed.: Diagnostic and Statistical Manual of Mental Disorders—III, American Psychiatric Association, May 1980. Bristol-Myers Squibb Company Princeton, NJ 08543 USA 818DIM-15 1115202A3 Revised November 2000 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 818DIM-15 1115202A3 BuSpar (buspirone HCl, USP) Patient Instruction Sheet Rx only HOW TO USE: BuSpar (buspirone HCl, USP) 15-mg and 30-mg Tablets in convenient DIVIDOSE® tablet form Response to buspirone varies among individuals. Your physician may find it necessary to adjust your dosage to obtain the proper response. This DIVIDOSE tablet design makes dosage adjustments easy. Each tablet is scored and can be broken accurately to provide any of the following dosages. If your doctor If your doctor prescribed the prescribed the the 30-mg tablet: 15-mg tablet: 30 mg 15 mg (the entire tablet) (the entire tablet) 20 mg 10 mg (two thirds of a tablet) (two thirds of a tablet) 10 mg 5 mg (one third of a tablet) (one third of a tablet) 15 mg 7.5 mg (one half of a tablet) (one half of a tablet) # 822 on 15-mg and 824 on 30-mg tablet To break a DIVIDOSE® tablet accurately and easily, hold the tablet between your thumbs and index fingers close to the appropriate tablet score (groove) as shown in the photo. Then, with the tablet score facing you, apply pressure and snap the tablet segments apart (segments breaking incorrectly should not be used). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bristol-Myers Squibb Company Princeton, NJ 08543 USA 818DIM-15 1115202A3 Revised May 2000 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:55.739972	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18731s39s45lbl.pdf', 'application_number': 18731, 'submission_type': 'SUPPL ', 'submission_number': 39}
11,308	NDA 18-731/S-043 Page 3 Bristol-Myers Squibb Company BuSpar® (buspirone HCl, USP) (Patient Instruction Sheet Included) DESCRIPTION BuSpar® (buspirone hydrochloride, USP) is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs. Buspirone hydrochloride is a white crystalline, water soluble compound with a molecular weight of 422.0. Chemically, buspirone hydrochloride is 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8- azaspiro[4.5]decane-7,9- dione monohydrochloride. The empirical formula C21H31N502 · HCl is represented by the following structural formula: BuSpar is supplied as tablets for oral administration containing 5 mg, 10 mg, 15 mg, or 30 mg of buspirone hydrochloride, USP (equivalent to 4.6 mg, 9.1 mg,13.7, and 27.4 mg of buspirone free base respectively). The 5-mg and 10-mg tablets are scored so they can be bisected. Thus, the 5-mg tablet can also provide a 2.5-mg dose, and the 10-mg tablet can provide a 5-mg dose. The 15-mg and 30-mg tablets are provided in the DIVIDOSE® tablet design. These tablets are scored so they can be either bisected or trisected. Thus, a single 15-mg tablet can provide the following doses: 15 mg (entire tablet), 10 mg (two thirds of a tablet), 7.5 mg (one half of a tablet), or 5 mg (one third of a tablet). A single 30-mg tablet can provide the following doses: 30 mg (entire tablet), 20 mg (two thirds of a tablet), 15 mg (one half of a tablet), or 10 mg (one third of a tablet). BuSpar Tablets contain the following inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 30-mg tablet also contains iron oxide. CLINICAL PHARMACOLOGY The mechanism of action of buspirone is unknown. Buspirone differs from typical benzodiazepine Rx only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 2 anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent sedative effect that is associated with more typical anxiolytics. In vitro preclinical studies have shown that buspirone has a high affinity for serotonin (5-HT1A) receptors. Buspirone has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models. Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmitter systems. BuSpar is rapidly absorbed in man and undergoes extensive first-pass metabolism. In a radiolabeled study, unchanged buspirone in the plasma accounted for only about 1% of the radioactivity in the plasma. Following oral administration, plasma concentrations of unchanged buspirone are very low and variable between subjects. Peak plasma levels of 1 to 6 ng/mL have been observed 40 to 90 minutes after single oral doses of 20 mg. The single-dose bioavailability of unchanged buspirone when taken as a tablet is on the average about 90% of an equivalent dose of solution, but there is large variability. The effects of food upon the bioavailability of BuSpar have been studied in eight subjects. They were given a 20-mg dose with and without food; the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of unchanged buspirone increased by 84% and 116% respectively, but the total amount of buspirone immunoreactive material did not change. This suggests that food may decrease the extent of presystemic clearance of buspirone. (see DOSAGE AND ADMINISTRATION section). A multiple-dose study conducted in 15 subjects suggests that buspirone has nonlinear pharmacokinetics. Thus, dose increases and repeated dosing may lead to somewhat higher blood levels of unchanged buspirone than would be predicted from results of single-dose studies. An in vitro protein binding study indicated that approximately 86% of buspirone is bound to plasma proteins. It was also observed that aspirin increased the plasma levels of free buspirone by 23%, while flurazepam decreased the plasma levels of free buspirone by 20%. However, it is not known whether these drugs cause similar effects on plasma levels of free buspirone in vivo, or whether such changes, if they do occur, cause clinically significant differences in treatment outcome. An in vitro study indicated that buspirone did not displace highly protein-bound drugs such as phenytoin, warfarin, and propranolol from plasma protein, and that buspirone may displace digoxin. Buspirone is metabolized primarily by oxidation, which in vitro has been shown to be mediated by cytochrome P450 3A4 (CYP3A4). (See PRECAUTIONS, Drug Interactions section.) Several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP), are produced. In animal models predictive of anxiolytic potential, 1-PP has about one quarter of the activity of buspirone, but is present in up to 20-fold greater amounts. However, this is probably not important in humans: blood samples from humans chronically exposed to BuSpar (buspirone hydrochloride) do not exhibit high levels of 1-PP; mean values are approximately 3 ng/mL and the highest human blood level recorded among 108 chronically dosed patients was 17 ng/mL, less than 1/200th of 1-PP levels found in animals given large doses of buspirone without signs of toxicity. In a single-dose study using 14C-labeled buspirone, 29% to 63% of the dose was excreted in the urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose. The average elimination half-life of unchanged buspirone after single doses of 10 to 40 mg is about 2 to 3 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 3 Special Populations Age and Gender Effects After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC and Cmax) were observed between elderly and younger subjects or between men and women. Hepatic Impairment After multiple-dose administration of buspirone to patients with hepatic impairment, steady-state AUC of buspirone increased 13-fold compared with healthy subjects (see PRECAUTIONS section). Renal Impairment After multiple-dose administration of buspirone to renally impaired (Clcr = 10-70 mL/min/1.73 m2) patients, steady-state AUC of buspirone increased 4-fold compared with healthy (Clcr ≥ 80 mL/min/1.73 m2) subjects (see PRECAUTIONS section). Race Effects The effects of race on the pharmacokinetics of buspirone have not been studied. INDICATIONS AND USAGE BuSpar is indicated for the management of anxiety disorders or 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. The efficacy of BuSpar has been demonstrated in controlled clinical trials of outpatients whose diagnosis roughly corresponds to Generalized Anxiety Disorder (GAD). Many of the patients enrolled in these studies also had coexisting depressive symptoms and BuSpar relieved anxiety in the presence of these coexisting depressive symptoms. The patients evaluated in these studies had experienced symptoms for periods of 1 month to over 1 year prior to the study, with an average symptom duration of 6 months. Generalized Anxiety Disorder (300.02) is described in the American Psychiatric Association's Diagnostic and Statistical Manual, III1 as follows: Generalized, persistent anxiety (of at least 1 month continual duration), manifested by symptoms from three of the four following categories: 1. Motor tension: shakiness, jitteriness, jumpiness, trembling, tension, muscle aches, fatigability, inability to relax, eyelid twitch, furrowed brow, strained face, fidgeting, restlessness, easy startle. 2. Autonomic hyperactivity: sweating, heart pounding or racing, cold, clammy hands, dry mouth, dizziness, lightheadedness, paresthesias (tingling in hands or feet), upset stomach, hot or cold spells, frequent urination, diarrhea, discomfort in the pit of the stomach, lump in the throat, flushing, pallor, high resting pulse and respiration rate. 3. Apprehensive expectation: anxiety, worry, fear, rumination, and anticipation of misfortune to self or others. 4. Vigilance and scanning: hyperattentiveness resulting in distractibility, difficulty in concentrating, insomnia, feeling "on edge," irritability, impatience. The above symptoms would not be due to another mental disorder, such as a depressive disorder or schizophrenia. However, mild depressive symptoms are common in GAD. The effectiveness of BuSpar in long-term use, that is, for more than 3 to 4 weeks, has not been demonstrated in controlled trials. There is no body of evidence available that systematically addresses the appropriate duration of treatment for GAD. However, in a study of long-term use, 264 patients were treated with BuSpar for 1 year without ill effect. Therefore, the physician who elects to use BuSpar for extended This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 4 periods should periodically reassess the usefulness of the drug for the individual patient. CONTRAINDICATIONS BuSpar is contraindicated in patients hypersensitive to buspirone hydrochloride. WARNINGS The administration of BuSpar to a patient taking a monoamine oxidase inhibitor (MAOI) may pose a hazard. There have been reports of the occurrence of elevated blood pressure when BuSpar (buspirone hydrochloride) has been added to a regimen including an MAOI. Therefore, it is recommended that BuSpar not be used concomitantly with an MAOI. Because BuSpar has no established antipsychotic activity, it should not be employed in lieu of appropriate antipsychotic treatment. PRECAUTIONS General Interference with Cognitive and Motor Performance Studies indicate that BuSpar is less sedating than other anxiolytics and that it does not produce significant functional impairment. However, its CNS effects in any individual patient may not be predictable. Therefore, patients should be cautioned about operating an automobile or using complex machinery until they are reasonably certain that buspirone treatment does not affect them adversely. While formal studies of the interaction of BuSpar (buspirone hydrochloride) with alcohol indicate that buspirone does not increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid concomitant use of alcohol and buspirone. Potential for Withdrawal Reactions in Sedative/Hypnotic/Anxiolytic Drug-Dependent Patients Because BuSpar does not exhibit cross-tolerance with benzodiazepines and other common sedative/hypnotic drugs, it will not block the withdrawal syndrome often seen with cessation of therapy with these drugs. Therefore, before starting therapy with BuSpar, it is advisable to withdraw patients gradually, especially patients who have been using a CNS-depressant drug chronically, from their prior treatment. Rebound or withdrawal symptoms may occur over varying time periods, depending in part on the type of drug, and its effective half-life of elimination. The syndrome of withdrawal from sedative/hypnotic/anxiolytic drugs can appear as any combination of irritability, anxiety, agitation, insomnia, tremor, abdominal cramps, muscle cramps, vomiting, sweating, flu-like symptoms without fever, and occasionally, even as seizures. Possible Concerns Related to Buspirone's Binding to Dopamine Receptors Because buspirone can bind to central dopamine receptors, a question has been raised about its potential to cause acute and chronic changes in dopamine-mediated neurological function (eg, dystonia, pseudo- parkinsonism, akathisia, and tardive dyskinesia). Clinical experience in controlled trials has failed to identify any significant neuroleptic-like activity; however, a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone-treated patients. The syndrome may be explained in several ways. For example, buspirone may increase central noradrenergic activity; alternatively, the effect may be attributable to dopaminergic effects (ie, represent akathisia). Obviously, the question cannot be totally resolved at this point in time. Generally, long-term sequelae of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 5 any drug's use can be identified only after several years of marketing. Information for Patients To assure safe and effective use of BuSpar, the following information and instructions should be given to patients: 1. Inform your physician about any medications, prescription or non-prescription, alcohol, or drugs that you are now taking or plan to take during your treatment with BuSpar. 2. Inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking BuSpar. 3. Inform your physician if you are breast-feeding an infant. 4. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery. 5. You should take BuSpar consistently, either always with or always without food. 6. During your treatment with BuSpar, avoid drinking large amounts of grapefruit juice. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions Psychotropic Agents MAO inhibitors: It is recommended that BuSpar (buspirone hydrochloride) not be used concomitantly with MAO inhibitors (see WARNINGS section). Amitriptyline: After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) of amitriptyline or its metabolite nortriptyline were observed. Diazepam: After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed. Haloperidol: In a study in normal volunteers, concomitant administration of buspirone and haloperidol resulted in increased serum haloperidol concentrations. The clinical significance of this finding is not clear. Nefazodone: [see Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4)] Trazodone: There is one report suggesting that the concomitant use of Desyrel® (trazodone hydrochloride) and buspirone may have caused 3- to 6-fold elevations on SGPT (ALT) in a few patients. In a similar study attempting to replicate this finding, no interactive effect on hepatic transaminases was identified. Triazolam/Flurazepam: Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 6 Other Psychotropics: Because the effects of concomitant administration of buspirone with most other psychotropic drugs have not been studied, the concomitant use of buspirone with other CNS-active drugs should be approached with caution. Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4) Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and the following: Diltiazem and Verapamil: In a study of nine healthy volunteers, coadministration of buspirone (10 mg as a single dose) with verapamil (80 mg t.i.d.) or diltiazem (60 mg t.i.d.) increased plasma buspirone concentrations (verapamil increased AUC and Cmax of buspirone 3.4-fold while diltiazem increased AUC and Cmax 5.3-fold and 4-fold, respectively.) Adverse events attributable to buspirone may be more likely during concomitant administration with either diltiazem or verapamil. Subsequent dose adjustment may be necessary and should be based on clinical assessment. Erythromycin: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5-fold increase in Cmax and 6-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg b.i.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Grapefruit Juice: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with grapefruit juice (200 mL double-strength t.i.d. for 2 days) increased plasma buspirone concentrations (4.3-fold increase in Cmax; 9.2-fold increase in AUC). Patients receiving buspirone should be advised to avoid drinking such large amounts of grapefruit juice. Itraconazole: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13-fold increase in Cmax and 19-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg q.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Nefazodone: In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg b.i.d.) with nefazodone (250 mg b.i.d.) resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in Cmax and up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP. With 5-mg b.i.d. doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and meta-chlorophenylpiperazine (9%). Slight increases in Cmax were observed for nefazodone (8%) and its metabolite HO-NEF (11%). Rifampin: In a study in healthy volunteers, coadministration of buspirone (30 mg as a single dose) with rifampin (600 mg/day for 5 days) decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. If the two drugs are to be used in combination, the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other Inhibitors and Inducers of CYP3A4: Substances that inhibit CYP3A4, such as ketoconazole or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 7 ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone, or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other Drugs Cimetidine: Coadministration of buspirone with cimetidine was found to increase Cmax (40%) and Tmax (2–fold), but had minimal effects on the AUC of buspirone. Protein Binding In vitro, buspirone does not displace tightly bound drugs like phenytoin, propranolol, and warfarin from serum proteins. However, there has been one report of prolonged prothrombin time when buspirone was added to the regimen of a patient treated with warfarin. The patient was also chronically receiving phenytoin, phenobarbital, digoxin, and Synthroid® . In vitro, buspirone may displace less firmly bound drugs like digoxin. The clinical significance of this property is unknown. Therapeutic levels of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol, thioridazine, and tolbutamide had only a limited effect on the extent of binding of buspirone to plasma proteins (see CLINICAL PHARMACOLOGY section). Drug/Laboratory Test Interactions Buspirone is not known to interfere with commonly employed clinical laboratory tests. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed in rats during a 24-month study at approximately 133 times the maximum recommended human oral dose; or in mice, during an 18-month study at approximately 167 times the maximum recommended human oral dose. With or without metabolic activation, buspirone did not induce point mutations in five strains of Salmonella typhimurium (Ames Test) or mouse lymphoma L5178YTK+ cell cultures, nor was DNA damage observed with buspirone in Wi-38 human cells. Chromosomal aberrations or abnormalities did not occur in bone marrow cells of mice given one or five daily doses of buspirone. Pregnancy: Teratogenic Effects Pregnancy Category B: No fertility impairment or fetal damage was observed in reproduction studies performed in rats and rabbits at buspirone doses of approximately 30 times the maximum recommended human dose. In humans, however, adequate and well-controlled studies during pregnancy have not been performed. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery The effect of BuSpar on labor and delivery in women is unknown. No adverse effects were noted in reproduction studies in rats. Nursing Mothers Synthroid® is the registered trademark of Knoll Pharmaceutical Company. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 8 The extent of the excretion in human milk of buspirone or its metabolites is not known. In rats, however, buspirone and its metabolites are excreted in milk. BuSpar administration to nursing women should be avoided if clinically possible. Pediatric Use The safety and effectiveness of BuSpar (buspirone hydrochloride) have not been determined in individuals below 18 years of age. The safety and effectiveness of buspirone were evaluated in two placebo-controlled 6-week trials involving a total of 559 pediatric patients (ranging from 6 to 17 years of age) with GAD. Doses studied were 7.5-30 mg b.i.d. (15-60 mg/day). There were no significant differences between buspirone and placebo with regard to the symptoms of GAD following doses recommended for the treatment of GAD in adults. Pharmacokinetic studies have shown that, for identical doses, plasma exposure to buspirone and its active metabolite, 1-PP, are equal to or higher in pediatric patients than adults. No unexpected safety findings were associated with buspirone in these trials. There are no long-term safety or efficacy data in this population. Geriatric Use In one study of 6632 patients who received Buspar for the treatment of anxiety, 605 patients were ≥ 65 years old and 41 were ≥ 75 years old; the safety and efficacy profiles for these 605 elderly patients (mean age =70.8 years) were similar to those in the younger population (mean age = 43.3 years). The rReview of other spontaneously reported adverse clinical events has not identified differences in reporting between elderly and younger patients, but greater sensitivity of some older patients can not be ruled out. There were no effects of age on the pharmacokinetics of buspirone (see CLINICAL PHARMACOLOGY, Special Populations section.) Use in Patients With Impaired Hepatic or Renal Function Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of BuSpar to patients with severe hepatic or renal impairment cannot be recommended (see CLINICAL PHARMACOLOGY section). ADVERSE REACTIONS (See also PRECAUTIONS) Commonly Observed The more commonly observed untoward events associated with the use of BuSpar not seen at an equivalent incidence among placebo-treated patients include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Associated with Discontinuation of Treatment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 9 One guide to the relative clinical importance of adverse events associated with BuSpar is provided by the frequency with which they caused drug discontinuation during clinical testing. Approximately 10% of the 2200 anxious patients who participated in the BuSpar premarketing clinical efficacy trials in anxiety disorders lasting 3 to 4 weeks discontinued treatment due to an adverse event. The more common events causing discontinuation included: central nervous system disturbances (3.4%), primarily dizziness, insomnia, nervousness, drowsiness, and lightheaded feeling; gastrointestinal disturbances (1.2%), primarily nausea; and miscellaneous disturbances (1.1%), primarily headache and fatigue. In addition, 3.4% of patients had multiple complaints, none of which could be characterized as primary. Incidence in Controlled Clinical Trials The table that follows enumerates adverse events that occurred at a frequency of 1% or more among BuSpar (buspirone hydrochloride) patients who participated in 4-week, controlled trials comparing BuSpar with placebo. The frequencies were obtained from pooled data for 17 trials. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. Comparison of the cited figures, however, does provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 10 TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS* (Percent of Patients Reporting) Adverse Experience BuSpar (n=477) Placebo (n=464) Cardiovascular Tachycardia/Palpitations 1 1 CNS Dizziness 12 3 Drowsiness 10 9 Nervousness 5 1 Insomnia 3 3 Lightheadedness 3 — Decreased Concentration 2 2 Excitement 2 — Anger/Hostility 2 — Confusion 2 — Depression 2 2 EENT Blurred Vision 2 — Gastrointestinal Nausea 8 5 Dry Mouth 3 4 Abdominal/Gastric Distress 2 2 Diarrhea 2 — Constipation 1 2 Vomiting 1 2 Musculoskeletal Musculoskeletal Aches/Pains 1 — Neurological Numbness 2 — Paresthesia 1 — Incoordination 1 — Tremor 1 — Skin Skin Rash 1 — Miscellaneous Headache 6 3 Fatigue 4 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 11 Weakness 2 — Sweating/Clamminess 1 — * Events reported by at least 1% of BuSpar patients are included. —Incidence less than 1%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 12 Other Events Observed During the Entire Premarketing Evaluation of BuSpar During its premarketing assessment, BuSpar was evaluated in over 3500 subjects. This section reports event frequencies for adverse events occurring in approximately 3000 subjects from this group who took multiple doses of BuSpar in the dose range for which BuSpar is being recommended (ie, the modal daily dose of BuSpar fell between 10 and 30 mg for 70% of the patients studied) and for whom safety data were systematically collected. The conditions and duration of exposure to BuSpar varied greatly, involving well- controlled studies as well as experience in open and uncontrolled clinical settings. As part of the total experience gained in clinical studies, various adverse events were reported. In the absence of appropriate controls in some of the studies, a causal relationship to BuSpar (buspirone hydrochloride) treatment cannot be determined. The list includes all undesirable events reasonably associated with the use of the drug. The following enumeration by organ system describes events in terms of their relative frequency of reporting in this data base. Events of major clinical importance are also described in the PRECAUTIONS section. The following definitions of frequency are used: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare events are those occurring in less than 1/1000 patients. Cardiovascular Frequent was nonspecific chest pain; infrequent were syncope, hypotension, and hypertension; rare were cerebrovascular accident, congestive heart failure, myocardial infarction, cardiomyopathy, and bradycardia. Central Nervous System Frequent were dream disturbances; infrequent were depersonalization, dysphoria, noise intolerance, euphoria, akathisia, fearfulness, loss of interest, dissociative reaction, hallucinations, involuntary movements, slowed reaction time, suicidal ideation, and seizures; rare were feelings of claustrophobia, cold intolerance, stupor, and slurred speech and psychosis. EENT Frequent were tinnitus, sore throat, and nasal congestion; infrequent were redness and itching of the eyes, altered taste, altered smell, and conjunctivitis; rare were inner ear abnormality, eye pain, photophobia, and pressure on eyes. Endocrine Rare were galactorrhea and thyroid abnormality. Gastrointestinal Infrequent were flatulence, anorexia, increased appetite, salivation, irritable colon, and rectal bleeding; rare was burning of the tongue. Genitourinary Infrequent were urinary frequency, urinary hesitancy, menstrual irregularity and spotting, and dysuria; rare were amenorrhea, pelvic inflammatory disease, enuresis, and nocturia. Musculoskeletal Infrequent were muscle cramps, muscle spasms, rigid/stiff muscles, and arthralgias; rare was muscle weakness. Respiratory Infrequent were hyperventilation, shortness of breath, and chest congestion; rare was epistaxis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 13 Sexual Function Infrequent were decreased or increased libido; rare were delayed ejaculation and impotence. Skin Infrequent were edema, pruritus, flushing, easy bruising, hair loss, dry skin, facial edema, and blisters; rare were acne and thinning of nails. Clinical Laboratory Infrequent were increases in hepatic aminotransferases (SGOT, SGPT); rare were eosinophilia, leukopenia, and thrombocytopenia. Miscellaneous Infrequent were weight gain, fever, roaring sensation in the head, weight loss, and malaise; rare were alcohol abuse, bleeding disturbance, loss of voice, and hiccoughs. POSTINTRODUCTION CLINICAL EXPERIENCE Postmarketing experience has shown an adverse experience profile similar to that given above. Voluntary reports since introduction have included rare occurrences of allergic reactions (including urticaria), angioedema, cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions, ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional lability, serotonin syndrome, transient difficulty with recall, urinary retention, and visual changes (including tunnel vision). Because of the uncontrolled nature of these spontaneous reports, a causal relationship to BuSpar treatment has not been determined. DRUG ABUSE AND DEPENDENCE Controlled Substance Class BuSpar (buspirone hydrochloride) is not a controlled substance. Physical and Psychological Dependence In human and animal studies, buspirone has shown no potential for abuse or diversion and there is no evidence that it causes tolerance, or either physical or psychological dependence. Human volunteers with a history of recreational drug or alcohol usage were studied in two double-blind clinical investigations. None of the subjects were able to distinguish between BuSpar and placebo. By contrast, subjects showed a statistically significant preference for methaqualone and diazepam. Studies in monkeys, mice, and rats have indicated that buspirone lacks potential for abuse. Following chronic administration in the rat, abrupt withdrawal of buspirone did not result in the loss of body weight commonly observed with substances that cause physical dependency. Although there is no direct evidence that BuSpar causes physical dependence or drug-seeking behavior, it is difficult to predict from experiments the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of BuSpar misuse or abuse (eg, development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Signs and Symptoms In clinical pharmacology trials, doses as high as 375 mg/day were administered to healthy male volunteers. As this dose was approached, the following symptoms were observed: nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. A few cases of overdosage have been reported, with complete recovery as the usual outcome. No deaths have been reported following overdosage with BuSpar alone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 14 Rare cases of intentional overdosage with a fatal outcome were invariably associated with ingestion of multiple drugs and/or alcohol, and a causal relationship to buspirone could not be determined. Toxicology studies of buspirone yielded the following LD50 values: mice, 655 mg/kg; rats, 196 mg/kg; dogs, 586 mg/kg; and monkeys, 356 mg/kg. These dosages are 160 to 550 times the recommended human daily dose. Recommended Overdose Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage. Respiration, pulse, and blood pressure should be monitored as in all cases of drug overdosage. No specific antidote is known to buspirone, and dialyzability of buspirone has not been determined. DOSAGE AND ADMINISTRATION The recommended initial dose is 15 mg daily (7.5 mg b.i.d.). To achieve an optimal therapeutic response, at intervals of 2 to 3 days the dosage may be increased 5 mg per day, as needed. The maximum daily dosage should not exceed 60 mg per day. In clinical trials allowing dose titration, divided doses of 20 to 30 mg per day were commonly employed. The bioavailability of buspirone is increased when given with food as compared to the fasted state (see CLINICAL PHARMACOLOGY section). Consequently, patients should take buspirone in a consistent manner with regard to the timing of dosing; either always with or always without food. When buspirone is to be given with a potent inhibitor of CYP3A4 the dosage recommendations described in the PRECAUTIONS: Drug Interactions section should be followed. HOW SUPPLIED BuSpar® (buspirone hydrochloride tablets, USP) Tablets, 5 mg and 10 mg (white, ovoid-rectangular with score, MJ logo, strength and the name BuSpar embossed) are available in bottles of 100 and 500, and in cartons containing 100 individually packaged tablets. 5-mg tablets NDC 0087-0818-41 Bottles of 100 NDC 0087-0818-44 Bottles of 500 NDC 0087-0818-43 Cartons of 100 unit dose 10-mg tablets NDC 0087-0819-41 Bottles of 100 NDC 0087-0819-44 Bottles of 500 Tablets, 15 mg white, in the DIVIDOSE® tablet design imprinted with the MJ logo, are available in bottles of 60 and 180. Tablets, 30 mg pink, in the DIVIDOSE® tablet design imprinted with the MJ logo, are available in bottles of 60. The 15-mg and 30-mg tablets are scored so that they can be either bisected or trisected. The 15-mg tablet has ID number 822 on one side and on the reverse side, the number 5 on each trisect segment. The 30-mg tablet has ID number 824 on one side and on the reverse side, the number 10 on each trisect segment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 15 15-mg tablets NDC 0087-0822-32 Bottles of 60 NDC 0087-0822-33 Bottles of 180 30-mg tablets NDC 0087-0824-81 Bottles of 60 U.S. Patent Nos. 5,015,646 and 6,008,222 Store at Room Temperature−Protect from temperatures greater than 86° F (30° C). Dispense in a tight, light-resistant container (USP). REFERENCE 1. American Psychiatric Association, Ed.: Diagnostic and Statistical Manual of Mental Disorders—III, American Psychiatric Association, May 1980. Bristol-Myers Squibb Company Princeton, NJ 08543 USA 818DIM-15 1115202A3 Revised November 2000 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 16 818DIM-15 1115202A3 BuSpar (buspirone HCl, USP) Patient Instruction Sheet Rx only HOW TO USE: BuSpar (buspirone HCl, USP) 15-mg and 30-mg Tablets in convenient DIVIDOSE® tablet form Response to buspirone varies among individuals. Your physician may find it necessary to adjust your dosage to obtain the proper response. This DIVIDOSE tablet design makes dosage adjustments easy. Each tablet is scored and can be broken accurately to provide any of the following dosages. If your doctor If your doctor prescribed the prescribed the the 30-mg tablet: 15-mg tablet: 30 mg 15 mg (the entire tablet) (the entire tablet) 20 mg 10 mg (two thirds of a tablet) (two thirds of a tablet) 10 mg 5 mg (one third of a tablet) (one third of a tablet) 15 mg 7.5 mg (one half of a tablet) (one half of a tablet) # 822 on 15-mg and 824 on 30-mg tablet To break a DIVIDOSE® tablet accurately and easily, hold the tablet between your thumbs and index fingers close to the appropriate tablet score (groove) as shown in the photo. Then, with the tablet score facing you, apply pressure and snap the tablet segments apart (segments breaking incorrectly should not be used). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA/Buspar/18731S43APLBL.doc 17 Bristol-Myers Squibb Company Princeton, NJ 08543 USA 818DIM-15 1115202A3 Revised May 2000 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:55.856175	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18731s43lbl.pdf', 'application_number': 18731, 'submission_type': 'SUPPL ', 'submission_number': 43}
11,309	company logo Rx only BuSpar® (buspirone HCl, USP) (Patient Instruction Sheet Included) DESCRIPTION BuSpar® (buspirone hydrochloride tablets, USP) is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs. Buspirone hydrochloride is a white crystalline, water soluble compound with a molecular weight of 422.0. Chemically, buspirone hydrochloride is 8-[4-[4-(2-pyrimidinyl)-1 piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione monohydrochloride. The empirical formula C21H31N5O2 • HCl is represented by the following structural formula: structural formula BuSpar is supplied as tablets for oral administration containing 5 mg, 10 mg, 15 mg, or 30 mg of buspirone hydrochloride, USP (equivalent to 4.6 mg, 9.1 mg, 13.7 mg, and 27.4 mg of buspirone free base, respectively). The 5 mg and 10 mg tablets are scored so they can be bisected. Thus, the 5 mg tablet can also provide a 2.5 mg dose, and the 10 mg tablet can provide a 5 mg dose. The 15 mg and 30 mg tablets are provided in the DIVIDOSE® tablet design. These tablets are scored so they can be either bisected or trisected. Thus, a single 15 mg tablet can provide the following doses: 15 mg (entire tablet), 10 mg (two thirds of a tablet), 7.5 mg (one half of a tablet), or 5 mg (one third of a tablet). A single 30 mg tablet can provide the following doses: 30 mg (entire tablet), 20 mg (two thirds of a tablet), 15 mg (one half of a tablet), or 10 mg (one third of a tablet). BuSpar Tablets contain the following inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 30 mg tablet also contains iron oxide. 1 Reference ID: 2867200 CLINICAL PHARMACOLOGY The mechanism of action of buspirone is unknown. Buspirone differs from typical benzodiazepine anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent sedative effect that is associated with more typical anxiolytics. In vitro preclinical studies have shown that buspirone has a high affinity for serotonin (5-HT1A) receptors. Buspirone has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models. Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmitter systems. BuSpar is rapidly absorbed in man and undergoes extensive first-pass metabolism. In a radiolabeled study, unchanged buspirone in the plasma accounted for only about 1% of the radioactivity in the plasma. Following oral administration, plasma concentrations of unchanged buspirone are very low and variable between subjects. Peak plasma levels of 1 ng/mL to 6 ng/mL have been observed 40 to 90 minutes after single oral doses of 20 mg. The single-dose bioavailability of unchanged buspirone when taken as a tablet is on the average about 90% of an equivalent dose of solution, but there is large variability. The effects of food upon the bioavailability of BuSpar have been studied in eight subjects. They were given a 20 mg dose with and without food; the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of unchanged buspirone increased by 84% and 116%, respectively, but the total amount of buspirone immunoreactive material did not change. This suggests that food may decrease the extent of presystemic clearance of buspirone (see DOSAGE AND ADMINISTRATION). A multiple-dose study conducted in 15 subjects suggests that buspirone has nonlinear pharmacokinetics. Thus, dose increases and repeated dosing may lead to somewhat higher blood levels of unchanged buspirone than would be predicted from results of single-dose studies. An in vitro protein binding study indicated that approximately 86% of buspirone is bound to plasma proteins. It was also observed that aspirin increased the plasma levels of free buspirone by 23%, while flurazepam decreased the plasma levels of free buspirone by 20%. However, it is not known whether these drugs cause similar effects on plasma levels 2 Reference ID: 2867200 of free buspirone in vivo, or whether such changes, if they do occur, cause clinically significant differences in treatment outcome. An in vitro study indicated that buspirone did not displace highly protein-bound drugs such as phenytoin, warfarin, and propranolol from plasma protein, and that buspirone may displace digoxin. Buspirone is metabolized primarily by oxidation, which in vitro has been shown to be mediated by cytochrome P450 3A4 (CYP3A4). (See PRECAUTIONS: Drug Interactions.) Several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP), are produced. In animal models predictive of anxiolytic potential, 1-PP has about one quarter of the activity of buspirone, but is present in up to 20-fold greater amounts. However, this is probably not important in humans: blood samples from humans chronically exposed to BuSpar (buspirone hydrochloride) do not exhibit high levels of 1-PP; mean values are approximately 3 ng/mL and the highest human blood level recorded among 108 chronically dosed patients was 17 ng/mL, less than 1/200th of 1-PP levels found in animals given large doses of buspirone without signs of toxicity. In a single-dose study using 14C-labeled buspirone, 29% to 63% of the dose was excreted in the urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose. The average elimination half-life of unchanged buspirone after single doses of 10 mg to 40 mg is about 2 to 3 hours. Special Populations Age and Gender Effects After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC and Cmax) were observed between elderly and younger subjects or between men and women. Hepatic Impairment After multiple-dose administration of buspirone to patients with hepatic impairment, steady-state AUC of buspirone increased 13-fold compared with healthy subjects (see PRECAUTIONS). 3 Reference ID: 2867200 Renal Impairment After multiple-dose administration of buspirone to renally impaired (Clcr = 10– 70 mL/min/1.73 m2) patients, steady-state AUC of buspirone increased 4-fold compared with healthy (Clcr ≥80 mL/min/1.73 m2) subjects (see PRECAUTIONS). Race Effects The effects of race on the pharmacokinetics of buspirone have not been studied. INDICATIONS AND USAGE BuSpar is indicated for the management of anxiety disorders or 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. The efficacy of BuSpar has been demonstrated in controlled clinical trials of outpatients whose diagnosis roughly corresponds to Generalized Anxiety Disorder (GAD). Many of the patients enrolled in these studies also had coexisting depressive symptoms and BuSpar relieved anxiety in the presence of these coexisting depressive symptoms. The patients evaluated in these studies had experienced symptoms for periods of 1 month to over 1 year prior to the study, with an average symptom duration of 6 months. Generalized Anxiety Disorder (300.02) is described in the American Psychiatric Association's Diagnostic and Statistical Manual, III1 as follows: Generalized, persistent anxiety (of at least 1 month continual duration), manifested by symptoms from three of the four following categories: 1. Motor tension: shakiness, jitteriness, jumpiness, trembling, tension, muscle aches, fatigability, inability to relax, eyelid twitch, furrowed brow, strained face, fidgeting, restlessness, easy startle. 2. Autonomic hyperactivity: sweating, heart pounding or racing, cold, clammy hands, dry mouth, dizziness, lightheadedness, paresthesias (tingling in hands or feet), upset stomach, hot or cold spells, frequent urination, diarrhea, discomfort in the pit of the stomach, lump in the throat, flushing, pallor, high resting pulse and respiration rate. 4 Reference ID: 2867200 3. Apprehensive expectation: anxiety, worry, fear, rumination, and anticipation of misfortune to self or others. 4. Vigilance and scanning: hyperattentiveness resulting in distractibility, difficulty in concentrating, insomnia, feeling "on edge," irritability, impatience. The above symptoms would not be due to another mental disorder, such as a depressive disorder or schizophrenia. However, mild depressive symptoms are common in GAD. The effectiveness of BuSpar in long-term use, that is, for more than 3 to 4 weeks, has not been demonstrated in controlled trials. There is no body of evidence available that systematically addresses the appropriate duration of treatment for GAD. However, in a study of long-term use, 264 patients were treated with BuSpar for 1 year without ill effect. Therefore, the physician who elects to use BuSpar for extended periods should periodically reassess the usefulness of the drug for the individual patient. CONTRAINDICATIONS BuSpar is contraindicated in patients hypersensitive to buspirone hydrochloride. WARNINGS The administration of BuSpar to a patient taking a monoamine oxidase inhibitor (MAOI) may pose a hazard. There have been reports of the occurrence of elevated blood pressure when BuSpar (buspirone hydrochloride) has been added to a regimen including an MAOI. Therefore, it is recommended that BuSpar not be used concomitantly with an MAOI. Because BuSpar has no established antipsychotic activity, it should not be employed in lieu of appropriate antipsychotic treatment. PRECAUTIONS General Interference with Cognitive and Motor Performance Studies indicate that BuSpar is less sedating than other anxiolytics and that it does not produce significant functional impairment. However, its CNS effects in any individual patient may not be predictable. Therefore, patients should be cautioned about operating an 5 Reference ID: 2867200 automobile or using complex machinery until they are reasonably certain that buspirone treatment does not affect them adversely. While formal studies of the interaction of BuSpar (buspirone hydrochloride) with alcohol indicate that buspirone does not increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid concomitant use of alcohol and buspirone. Potential for Withdrawal Reactions in Sedative/Hypnotic/Anxiolytic Drug- Dependent Patients Because BuSpar does not exhibit cross-tolerance with benzodiazepines and other common sedative/hypnotic drugs, it will not block the withdrawal syndrome often seen with cessation of therapy with these drugs. Therefore, before starting therapy with BuSpar, it is advisable to withdraw patients gradually, especially patients who have been using a CNS-depressant drug chronically, from their prior treatment. Rebound or withdrawal symptoms may occur over varying time periods, depending in part on the type of drug, and its effective half-life of elimination. The syndrome of withdrawal from sedative/hypnotic/anxiolytic drugs can appear as any combination of irritability, anxiety, agitation, insomnia, tremor, abdominal cramps, muscle cramps, vomiting, sweating, flu-like symptoms without fever, and occasionally, even as seizures. Possible Concerns Related to Buspirone's Binding to Dopamine Receptors Because buspirone can bind to central dopamine receptors, a question has been raised about its potential to cause acute and chronic changes in dopamine-mediated neurological function (eg, dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia). Clinical experience in controlled trials has failed to identify any significant neuroleptic-like activity; however, a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone-treated patients. The syndrome may be explained in several ways. For example, buspirone may increase central noradrenergic activity; alternatively, the effect may be attributable to dopaminergic effects (ie, represent akathisia). See ADVERSE REACTIONS: Postmarketing Experience. 6 Reference ID: 2867200 Information for Patients To assure safe and effective use of BuSpar, the following information and instructions should be given to patients: 1. Inform your physician about any medications, prescription or non-prescription, alcohol, or drugs that you are now taking or plan to take during your treatment with BuSpar. 2. Inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking BuSpar. 3. Inform your physician if you are breast-feeding an infant. 4. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery. 5. You should take BuSpar (buspirone hydrochloride) consistently, either always with or always without food. 6. During your treatment with BuSpar, avoid drinking large amounts of grapefruit juice. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions Psychotropic Agents MAO inhibitors: It is recommended that BuSpar not be used concomitantly with MAO inhibitors (see WARNINGS). Amitriptyline: After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) of amitriptyline or its metabolite nortriptyline were observed. Diazepam: After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) were observed for diazepam, but increases of about 15% were seen for 7 Reference ID: 2867200 nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed. Haloperidol: In a study in normal volunteers, concomitant administration of buspirone and haloperidol resulted in increased serum haloperidol concentrations. The clinical significance of this finding is not clear. Nefazodone: (see Inhibitors and Inducers of Cytochrome P450 3A4 [CYP3A4]) Trazodone: There is one report suggesting that the concomitant use of Desyrel® (trazodone hydrochloride) and buspirone may have caused 3- to 6-fold elevations on SGPT (ALT) in a few patients. In a similar study attempting to replicate this finding, no interactive effect on hepatic transaminases was identified. Triazolam/Flurazepam: Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine. Other Psychotropics: Because the effects of concomitant administration of buspirone with most other psychotropic drugs have not been studied, the concomitant use of buspirone with other CNS-active drugs should be approached with caution. Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4) Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and the following: Diltiazem and Verapamil: In a study of nine healthy volunteers, coadministration of buspirone (10 mg as a single dose) with verapamil (80 mg t.i.d.) or diltiazem (60 mg t.i.d.) increased plasma buspirone concentrations (verapamil increased AUC and Cmax of buspirone 3.4-fold while diltiazem increased AUC and Cmax 5.5-fold and 4-fold, respectively.) Adverse events attributable to buspirone may be more likely during concomitant administration with either diltiazem or verapamil. Subsequent dose adjustment may be necessary and should be based on clinical assessment. Erythromycin: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5-fold increase in Cmax and 6-fold increase in AUC). These 8 Reference ID: 2867200 pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg b.i.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Grapefruit Juice: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with grapefruit juice (200 mL double-strength t.i.d. for 2 days) increased plasma buspirone concentrations (4.3-fold increase in Cmax; 9.2-fold increase in AUC). Patients receiving buspirone should be advised to avoid drinking such large amounts of grapefruit juice. Itraconazole: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13-fold increase in Cmax and 19-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg q.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Nefazodone: In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg b.i.d.) with nefazodone (250 mg b.i.d.) resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in Cmax and up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP. With 5 mg b.i.d. doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and meta-chlorophenylpiperazine (9%). Slight increases in Cmax were observed for nefazodone (8%) and its metabolite HO-NEF (11%). Subjects receiving buspirone 5 mg b.i.d. and nefazodone 250 mg b.i.d experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg q.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Rifampin: In a study in healthy volunteers, coadministration of buspirone (30 mg as a single dose) with rifampin (600 mg/day for 5 days) decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of 9 Reference ID: 2867200 buspirone. If the two drugs are to be used in combination, the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other Inhibitors and Inducers of CYP3A4: Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other Drugs Cimetidine: Coadministration of buspirone with cimetidine was found to increase Cmax (40%) and Tmax (2-fold), but had minimal effects on the AUC of buspirone. Protein Binding In vitro, buspirone does not displace tightly bound drugs like phenytoin, propranolol, and warfarin from serum proteins. However, there has been one report of prolonged prothrombin time when buspirone was added to the regimen of a patient treated with warfarin. The patient was also chronically receiving phenytoin, phenobarbital, digoxin, and Synthroid® . In vitro, buspirone may displace less firmly bound drugs like digoxin. The clinical significance of this property is unknown. Therapeutic levels of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol, thioridazine, and tolbutamide had only a limited effect on the extent of binding of buspirone to plasma proteins (see CLINICAL PHARMACOLOGY). Drug/Laboratory Test Interactions Buspirone hydrochloride may interfere with the urinary metanephrine/catecholamine assay. It has been mistakenly read as metanephrine during routine assay testing for pheochromocytoma, resulting in a false positive laboratory result. Buspirone 10 Reference ID: 2867200 hydrochloride should therefore be discontinued for at least 48 hours prior to undergoing a urine collection for catecholamines. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed in rats during a 24-month study at approximately 133 times the maximum recommended human oral dose; or in mice, during an 18-month study at approximately 167 times the maximum recommended human oral dose. With or without metabolic activation, buspirone did not induce point mutations in five strains of Salmonella typhimurium (Ames Test) or mouse lymphoma L5178YTK+ cell cultures, nor was DNA damage observed with buspirone in Wi-38 human cells. Chromosomal aberrations or abnormalities did not occur in bone marrow cells of mice given one or five daily doses of buspirone. Pregnancy: Teratogenic Effects Pregnancy Category B: No fertility impairment or fetal damage was observed in reproduction studies performed in rats and rabbits at buspirone doses of approximately 30 times the maximum recommended human dose. In humans, however, adequate and well- controlled studies during pregnancy have not been performed. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery The effect of BuSpar (buspirone hydrochloride) on labor and delivery in women is unknown. No adverse effects were noted in reproduction studies in rats. Nursing Mothers The extent of the excretion in human milk of buspirone or its metabolites is not known. In rats, however, buspirone and its metabolites are excreted in milk. BuSpar administration to nursing women should be avoided if clinically possible. 11 Reference ID: 2867200 Pediatric Use The safety and effectiveness of buspirone were evaluated in two placebo-controlled 6-week trials involving a total of 559 pediatric patients (ranging from 6 to 17 years of age) with GAD. Doses studied were 7.5 mg to 30 mg b.i.d. (15–60 mg/day). There were no significant differences between buspirone and placebo with regard to the symptoms of GAD following doses recommended for the treatment of GAD in adults. Pharmacokinetic studies have shown that, for identical doses, plasma exposure to buspirone and its active metabolite, 1-PP, are equal to or higher in pediatric patients than adults. No unexpected safety findings were associated with buspirone in these trials. There are no long-term safety or efficacy data in this population. Geriatric Use In one study of 6632 patients who received buspirone for the treatment of anxiety, 605 patients were ≥65 years old and 41 were ≥75 years old; the safety and efficacy profiles for these 605 elderly patients (mean age = 70.8 years) were similar to those in the younger population (mean age = 43.3 years). Review of spontaneously reported adverse clinical events has not identified differences between elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out. There were no effects of age on the pharmacokinetics of buspirone (see CLINICAL PHARMACOLOGY: Special Populations). Use in Patients With Impaired Hepatic or Renal Function Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of BuSpar to patients with severe hepatic or renal impairment cannot be recommended (see CLINICAL PHARMACOLOGY). 12 Reference ID: 2867200 ADVERSE REACTIONS (See also PRECAUTIONS) Commonly Observed The more commonly observed untoward events associated with the use of BuSpar not seen at an equivalent incidence among placebo-treated patients include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Associated with Discontinuation of Treatment One guide to the relative clinical importance of adverse events associated with BuSpar is provided by the frequency with which they caused drug discontinuation during clinical testing. Approximately 10% of the 2200 anxious patients who participated in the BuSpar premarketing clinical efficacy trials in anxiety disorders lasting 3 to 4 weeks discontinued treatment due to an adverse event. The more common events causing discontinuation included: central nervous system disturbances (3.4%), primarily dizziness, insomnia, nervousness, drowsiness, and lightheaded feeling; gastrointestinal disturbances (1.2%), primarily nausea; and miscellaneous disturbances (1.1%), primarily headache and fatigue. In addition, 3.4% of patients had multiple complaints, none of which could be characterized as primary. Incidence in Controlled Clinical Trials The table that follows enumerates adverse events that occurred at a frequency of 1% or more among BuSpar (buspirone hydrochloride) patients who participated in 4-week, controlled trials comparing BuSpar with placebo. The frequencies were obtained from pooled data for 17 trials. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. Comparison of the cited figures, however, does provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. 13 Reference ID: 2867200 TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS* (Percent of Patients Reporting) BuSpar Placebo Adverse Experience (n=477) (n=464) Cardiovascular Tachycardia/Palpitations 1 1 CNS Dizziness 12 3 Drowsiness 10 9 Nervousness 5 1 Insomnia 3 3 Lightheadedness 3 — Decreased Concentration 2 2 Excitement 2 — Anger/Hostility 2 — Confusion 2 — Depression 2 2 EENT Blurred Vision 2 — Gastrointestinal Nausea 8 5 Dry Mouth 3 4 Abdominal/Gastric Distress 2 2 Diarrhea 2 — Constipation 1 2 Vomiting 1 2 Musculoskeletal Musculoskeletal Aches/Pains 1 — Neurological Numbness 2 — Paresthesia 1 — Incoordination 1 — Tremor 1 — Skin Skin Rash 1 — Miscellaneous Headache 6 3 Fatigue 4 4 Weakness 2 — Sweating/Clamminess 1 — *Events reported by at least 1% of BuSpar patients are included. —Incidence less than 1%. Other Events Observed During the Entire Premarketing Evaluation of BuSpar During its premarketing assessment, BuSpar was evaluated in over 3500 subjects. This section reports event frequencies for adverse events occurring in approximately 3000 14 Reference ID: 2867200 subjects from this group who took multiple doses of BuSpar in the dose range for which BuSpar is being recommended (ie, the modal daily dose of BuSpar fell between 10 mg and 30 mg for 70% of the patients studied) and for whom safety data were systematically collected. The conditions and duration of exposure to BuSpar varied greatly, involving well-controlled studies as well as experience in open and uncontrolled clinical settings. As part of the total experience gained in clinical studies, various adverse events were reported. In the absence of appropriate controls in some of the studies, a causal relationship to BuSpar (buspirone hydrochloride) treatment cannot be determined. The list includes all undesirable events reasonably associated with the use of the drug. The following enumeration by organ system describes events in terms of their relative frequency of reporting in this data base. Events of major clinical importance are also described in the PRECAUTIONS section. The following definitions of frequency are used: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare events are those occurring in less than 1/1000 patients. Cardiovascular Frequent was nonspecific chest pain; infrequent were syncope, hypotension, and hypertension; rare were cerebrovascular accident, congestive heart failure, myocardial infarction, cardiomyopathy, and bradycardia. Central Nervous System Frequent were dream disturbances; infrequent were depersonalization, dysphoria, noise intolerance, euphoria, akathisia, fearfulness, loss of interest, dissociative reaction, hallucinations, involuntary movements, slowed reaction time, suicidal ideation, and seizures; rare were feelings of claustrophobia, cold intolerance, stupor, and slurred speech and psychosis. EENT Frequent were tinnitus, sore throat, and nasal congestion; infrequent were redness and itching of the eyes, altered taste, altered smell, and conjunctivitis; rare were inner ear abnormality, eye pain, photophobia, and pressure on eyes. 15 Reference ID: 2867200 Endocrine Rare were galactorrhea and thyroid abnormality. Gastrointestinal Infrequent were flatulence, anorexia, increased appetite, salivation, irritable colon, and rectal bleeding; rare was burning of the tongue. Genitourinary Infrequent were urinary frequency, urinary hesitancy, menstrual irregularity and spotting, and dysuria; rare were amenorrhea, pelvic inflammatory disease, enuresis, and nocturia. Musculoskeletal Infrequent were muscle cramps, muscle spasms, rigid/stiff muscles, and arthralgias; rare was muscle weakness. Respiratory Infrequent were hyperventilation, shortness of breath, and chest congestion; rare was epistaxis. Sexual Function Infrequent were decreased or increased libido; rare were delayed ejaculation and impotence. Skin Infrequent were edema, pruritus, flushing, easy bruising, hair loss, dry skin, facial edema, and blisters; rare were acne and thinning of nails. Clinical Laboratory Infrequent were increases in hepatic aminotransferases (SGOT, SGPT); rare were eosinophilia, leukopenia, and thrombocytopenia. Miscellaneous Infrequent were weight gain, fever, roaring sensation in the head, weight loss, and malaise; rare were alcohol abuse, bleeding disturbance, loss of voice, and hiccoughs. 16 Reference ID: 2867200 Postmarketing Experience Postmarketing experience has shown an adverse experience profile similar to that given above. Voluntary reports since introduction have included rare occurrences of allergic reactions (including urticaria), angioedema, cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions (including dystonia), ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional lability, serotonin syndrome, transient difficulty with recall, urinary retention, visual changes (including tunnel vision), parkinsonism, akathisia, restless leg syndrome, and restlessness. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to BuSpar treatment has not been determined. DRUG ABUSE AND DEPENDENCE Controlled Substance Class BuSpar (buspirone hydrochloride) is not a controlled substance. Physical and Psychological Dependence In human and animal studies, buspirone has shown no potential for abuse or diversion and there is no evidence that it causes tolerance, or either physical or psychological dependence. Human volunteers with a history of recreational drug or alcohol usage were studied in two double-blind clinical investigations. None of the subjects were able to distinguish between BuSpar and placebo. By contrast, subjects showed a statistically significant preference for methaqualone and diazepam. Studies in monkeys, mice, and rats have indicated that buspirone lacks potential for abuse. Following chronic administration in the rat, abrupt withdrawal of buspirone did not result in the loss of body weight commonly observed with substances that cause physical dependency. Although there is no direct evidence that BuSpar causes physical dependence or drug-seeking behavior, it is difficult to predict from experiments the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of BuSpar misuse or abuse (eg, development of tolerance, incrementation of dose, drug-seeking behavior). 17 Reference ID: 2867200 OVERDOSAGE Signs and Symptoms In clinical pharmacology trials, doses as high as 375 mg/day were administered to healthy male volunteers. As this dose was approached, the following symptoms were observed: nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. A few cases of overdosage have been reported, with complete recovery as the usual outcome. No deaths have been reported following overdosage with BuSpar alone. Rare cases of intentional overdosage with a fatal outcome were invariably associated with ingestion of multiple drugs and/or alcohol, and a causal relationship to buspirone could not be determined. Toxicology studies of buspirone yielded the following LD50 values: mice, 655 mg/kg; rats, 196 mg/kg; dogs, 586 mg/kg; and monkeys, 356 mg/kg. These dosages are 160 to 550 times the recommended human daily dose. Recommended Overdose Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage. Respiration, pulse, and blood pressure should be monitored as in all cases of drug overdosage. No specific antidote is known to buspirone, and dialyzability of buspirone has not been determined. DOSAGE AND ADMINISTRATION The recommended initial dose is 15 mg daily (7.5 mg b.i.d.). To achieve an optimal therapeutic response, at intervals of 2 to 3 days the dosage may be increased 5 mg per day, as needed. The maximum daily dosage should not exceed 60 mg per day. In clinical trials allowing dose titration, divided doses of 20 mg to 30 mg per day were commonly employed. The bioavailability of buspirone is increased when given with food as compared to the fasted state (see CLINICAL PHARMACOLOGY). Consequently, patients should take buspirone in a consistent manner with regard to the timing of dosing; either always with or always without food. When buspirone is to be given with a potent inhibitor of CYP3A4, the dosage recommendations described in the PRECAUTIONS: Drug Interactions section should be followed. 18 Reference ID: 2867200 HOW SUPPLIED BuSpar® (buspirone hydrochloride tablets, USP) Tablets, 5 mg and 10 mg (white, ovoid- rectangular with score, MJ logo, strength and the name BuSpar embossed) are available in bottles of 100. 5 mg tablets NDC 0087-0818-41 Bottles of 100 10 mg tablets NDC 0087-0819-41 Bottles of 100 Tablets, 15 mg white, in the DIVIDOSE® tablet design imprinted with the MJ logo, are available in bottles of 60 and 180. Tablets, 30 mg pink, in the DIVIDOSE® tablet design imprinted with the MJ logo, are available in bottles of 60. The 15 mg and 30 mg tablets are scored so that they can be either bisected or trisected. The 15 mg tablet has ID number 822 on one side and on the reverse side, the number 5 on each trisect segment. The 30 mg tablet has ID number 824 on one side and on the reverse side, the number 10 on each trisect segment. 15 mg tablets NDC 0087-0822-32 Bottles of 60 NDC 0087-0822-33 Bottles of 180 30 mg tablets NDC 0087-0824-81 Bottles of 60 Store at 25° C (77° F); excursions permitted between 15° C to 30° C (59° F to 86° F) [see USP controlled room temperature]. Dispense in a tight, light-resistant container (USP). REFERENCE 1. American Psychiatric Association, Ed.: Diagnostic and Statistical Manual of Mental Disorders—III, American Psychiatric Association, May 1980. Synthroid® is the registered trademark of Abbott Laboratories. Bristol-Myers Squibb Company Princeton, NJ 08543 USA Rev November 2010 19 Reference ID: 2867200 pill illustrations BuSpar® (buspirone HCl, USP) Patient Instruction Sheet Rx only HOW TO USE: BuSpar® (buspirone HCl, USP) 15 mg and 30 mg Tablets in convenient DIVIDOSE® tablet form Response to buspirone varies among individuals. Your physician may find it necessary to adjust your dosage to obtain the proper response. This DIVIDOSE tablet design makes dosage adjustments easy. Each tablet is scored and can be broken accurately to provide any of the following dosages. If your doctor If your doctor prescribed the prescribed the 30 mg tablet: 15 mg tablet: 30 mg 15 mg (the entire tablet) (the entire tablet) 20 mg 10 mg (two thirds of a tablet) (two thirds of a tablet) 10 mg 5 mg (one third of a tablet) (one third of a tablet) 15 mg 7.5 mg (one half of a tablet) (one half of a tablet) #822 on 15 mg and 824 on 30 mg tablet To break a DIVIDOSE tablet accurately and easily, hold the tablet between your thumbs and index fingers close to the appropriate tablet score (groove) as shown in the photo. 20 Reference ID: 2867200 Then, with the tablet score facing you, apply pressure and snap the tablet segments apart (segments breaking incorrectly should not be used). usage illustration Bristol-Myers Squibb Company Princeton, NJ 08543 USA Rev November 2010 21 Reference ID: 2867200	custom-source	2025-02-12T13:44:55.888663	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018731s051lbl.pdf', 'application_number': 18731, 'submission_type': 'SUPPL ', 'submission_number': 51}
11,310	TALWIN® Nx CIV pentazocine and naloxone hydrochlorides, USP Analgesic for Oral Use Only TALWIN® Nx is intended for oral use only. Severe, potentially lethal, reactions may result from misuse of TALWIN® Nx by injection either alone or in combination with other substances. (See DRUG ABUSE AND DEPENDENCE section.) DESCRIPTION TALWIN Nx (pentazocine and naloxone hydrochlorides, USP) contains pentazocine hydrochloride, USP, equivalent to 50 mg base and is a member of the benzazocine series (also known as the benzomorphan series), and naloxone hydrochloride, USP, equivalent to 0.5 mg base. TALWIN Nx is an analgesic for oral administration. Chemically, pentazocine hydrochloride is (2R,6R,11R*)-1,2, 3, 4, 5, 6 Hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride, a white, crystalline substance soluble in acidic aqueous solutions, and has the following structural formula: Chemical Structure C19H27NO·HCl M.W. 321.88 Chemically, naloxone hydrochloride is Morphinan-6-one, 4, 5-epoxy-3, 14 dihydroxy-17-(2-propenyl)-, hydrochloride, (5α)-. It is a slightly off-white powder, and is soluble in water and dilute acids, and has the following structural formula: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chemical Structure C19H21NO4·HCl M.W.=363.84 Inactive Ingredients: Colloidal Silicon Dioxide, Dibasic Calcium Phosphate, D&C Yellow #10, FD&C Yellow #6, Magnesium Stearate, Microcrystalline Cellulose, Sodium Lauryl Sulfate, Starch. CLINICAL PHARMACOLOGY Pentazocine is a potent analgesic which when administered orally in a 50 mg dose appears equivalent in analgesic effect to 60 mg (1 grain) of codeine. Onset of significant analgesia usually occurs between 15 and 30 minutes after oral administration, and duration of action is usually three hours or longer. Onset and duration of action and the degree of pain relief are related both to dose and the severity of pretreatment pain. Pentazocine weakly antagonizes the analgesic effects of morphine and meperidine; in addition, it produces incomplete reversal of cardiovascular, respiratory, and behavioral depression induced by morphine and meperidine. Pentazocine has about 1/50 the antagonistic activity of nalorphine. It also has sedative activity. Pentazocine is well absorbed from the gastrointestinal tract. Concentrations in plasma coincide closely with the onset, duration, and intensity of analgesia; peak values occur 1 to 3 hours after oral administration. The half-life in plasma is 2 to 3 hours. Pentazocine is metabolized in the liver and excreted primarily in the urine. Pentazocine passes into the fetal circulation. Naloxone when administered orally at 0.5 mg has no pharmacologic activity. Naloxone hydrochloride administered parenterally at the same dose is an effective antagonist to pentazocine and a pure antagonist to narcotic analgesics. TALWIN Nx is a potent analgesic when administered orally. However, the presence of naloxone in TALWIN Nx will prevent the effect of pentazocine if the product is misused by injection. Studies in animals indicate that the presence of naloxone does not affect pentazocine analgesia when the combination is given orally. If the combination is given by injection the action of pentazocine is neutralized. INDICATIONS AND USAGE TALWIN® Nx is intended for oral use only. Severe, potentially lethal, reactions may result from misuse of TALWIN® Nx by injection either alone or in combination with other substances. (See DRUG ABUSE AND DEPENDENCE section.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TALWIN Nx (pentazocine and naloxone hydrochlorides, USP) is indicated for the relief of moderate to severe pain. TALWIN Nx is indicated for oral use only. CONTRAINDICATIONS TALWIN Nx should not be administered to patients who are hypersensitive to either pentazocine or naloxone. TALWIN® Nx is intended for oral use only. Severe, potentially lethal, reactions may result from misuse of TALWIN® Nx by injection either alone or in combination with other substances. (See DRUG ABUSE AND DEPENDENCE section.) WARNINGS Drug Dependence. Pentazocine can cause a physical and psychological dependence. (See DRUG ABUSE AND DEPENDENCE.) Head Injury and Increased Intracranial Pressure. As in the case of other potent analgesics, the potential of pentazocine for elevating cerebrospinal fluid pressure may be attributed to CO2 retention due to the respiratory depressant effects of the drug. These effects may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial pressure. Furthermore, pentazocine can produce effects which may obscure the clinical course of patients with head injuries. In such patients, pentazocine must be used with extreme caution and only if its use is deemed essential. Usage with Alcohol. Due to the potential for increased CNS depressants effects, alcohol should be used with caution in patients who are currently receiving pentazocine. Patients Receiving Narcotics. Pentazocine is a mild narcotic antagonist. Some patients previously given narcotics, including methadone for the daily treatment of narcotic dependence, have experienced withdrawal symptoms after receiving pentazocine. Certain Respiratory Conditions. Although respiratory depression has rarely been reported after oral administration of pentazocine, the drug should be administered with caution to patients with respiratory depression from any cause, severely limited respiratory reserve, severe bronchial asthma, and other obstructive respiratory conditions, or cyanosis. Acute CNS Manifestations. Patients receiving therapeutic doses of pentazocine have experienced hallucinations (usually visual), disorientation, and confusion which have cleared spontaneously within a period of hours. The mechanism of this reaction is not known. Such patients should be very closely observed and vital signs checked. If the drug is reinstituted, it should be done with caution since these acute CNS manifestations may recur. PRECAUTIONS CNS Effect. Caution should be used when pentazocine is administered to patients prone to seizures; seizures have occurred in a few such patients in association with the use of pentazocine though no cause and effect relationship has been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Porphyria. Particular caution should be exercised in administering pentazocine to patients with porphyria since it may provoke an acute attack in susceptible individuals. Cardiovascular Disease. Pentazocine can elevate blood pressure, possibly through the release of endogenous catecholamines. Particular caution should be exercised in conditions where alterations in vascular resistance and blood pressure might be particularly undesirable, such as in the acute phase of myocardial infarction. As with all drugs, pentazocine should be used with caution in patients with myocardial infarction who have nausea or vomiting. Impaired Renal or Hepatic Function. Decreased metabolism of pentazocine by the liver in extensive liver disease may predispose to accentuation of side effects. Although laboratory tests have not indicated that pentazocine causes or increases renal or hepatic impairment, the drug should be administered with caution to patients with such impairment. In prescribing pentazocine for long-term use, the physician should take precautions to avoid increases in dose by the patient. Other. Caution should also be observed when administering pentazocine in patients with hypothyroidism, adrenocortical insufficiency, prostate hypertrophy, inflammatory or obstructive bowel disease, acute abdominal syndromes of unknown etiology, cholecystitis, pancreatitis, or acute alcohol intoxication and delirium tremens. Biliary Surgery. Narcotic drug products are generally considered to elevate biliary tract pressure for varying periods following their administration. Some evidence suggests that pentazocine may differ from other marketed narcotics in this respect (i.e., it causes little or no elevation in biliary tract pressures). The clinical significance of these findings, however, is not yet known. Information for Patients. Since sedation, dizziness, and occasional euphoria have been noted, ambulatory patients should be warned not to operate machinery, drive cars, or unnecessarily expose themselves to hazards. Pentazocine may cause physical and psychological dependence when taken alone and may have additive CNS depressant properties when taken in combination with alcohol or other CNS depressants. Drug Interactions. Concomitant use of monoamine oxidase inhibitors (MAOIs) with pentazocine may cause CNS excitation and hypertension through their respective effects on catecholamines. Caution should therefore be observed in administering pentazocine to patients who are currently receiving MAOIs or who have received them within the preceding 14 days. Agents with CNS depressant properties including phenothiazine, tricyclic antidepressants, and ethyl alcohol can enhance the central nervous system depressant effects of pentazocine (See WARNINGS). Tobacco smoking could enhance the metabolic clearance rate of pentazocine reducing the clinical effectiveness of a standard dose of pentazocine. Pentazocine can antagonize the effects of opiate agonists such as diamorphine, morphine, and heroin and is itself antagonized by naloxone. Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term studies in animals to test for carcinogenesis have been performed with the components of TALWIN Nx. Pregnancy Category C. In animal reproduction studies (rodents), teratogenic effects were reported only at doses high enough to cause maternal toxicity. The safe use of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pentazocine in pregnant women (other than during labor) has not been established. TALWIN Nx should be given to pregnant women only if clearly needed. Labor and Delivery. Patients receiving pentazocine during labor have experienced no adverse effects other than those that occur with commonly used analgesics. However, pentazocine can cross the placental barrier and cause central nervous system depression in the newborn and, if used regularly throughout pregnancy, may lead to symptoms of withdrawal in the newborn. TALWIN Nx should be used with caution in women delivering premature infants. The effect of TALWIN Nx on the mother and fetus, the duration of labor or delivery, the possibility that forceps delivery or other intervention or resuscitation of the newborn may be necessary, or the effect of TALWIN Nx on the later growth, development, and functional maturation of the child are unknown at the present time. Nursing Mothers. Pentazocine is excreted in human milk. Caution should be exercised when TALWIN Nx is administered to a nursing woman. Pediatric Use. Safety and effectiveness in pediatric patients below the age of 12 years have not been established. Geriatric Use. Controlled clinical studies of TALWIN NX 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 or effectiveness in analgesic activity 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 Cardiovascular. Hypertension, hypotension, circulatory depression, tachycardia, syncope. Respiratory. Rarely, respiratory depression. Acute CNS Manifestations. Patients receiving therapeutic doses of pentazocine have experienced hallucinations (usually visual), disorientation, and confusion which have cleared spontaneously within a period of hours. The mechanism of this reaction is not known. Such patients should be closely observed and vital signs checked. If the drug is reinstituted it should be done with caution since these acute CNS manifestations may recur. Other CNS Effects. Grand mal convulsions, increase in intracranial pressure, dizziness, lightheadedness, hallucinations, sedation, euphoria, headache, confusion, disorientation; infrequently weakness, disturbed dreams, insomnia, syncope, visual blurring and focusing difficulty, depression; and rarely tremor, irritability, excitement, tinnitus. Autonomic. Sweating; infrequently flushing; and rarely chills. Gastrointestinal. Nausea, vomiting, constipation, diarrhea, anorexia, dry mouth, biliary tract spasm, and rarely abdominal distress. Allergic. Edema of the face; anaphylactic shock; dermatitis, including pruritus; flushed skin, including plethora; infrequently rash, and rarely urticaria. Ophthalmic. Visual blurring and focusing difficulty, miosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hematologic. Depression of white blood cells (especially granulocytes), with rare cases of agranulocytosis, which is usually reversible, moderate transient eosinophilia. Dependence and Withdrawal Symptoms. (See WARNINGS, PRECAUTIONS, and DRUG ABUSE AND DEPENDENCE Sections). Other. Headache, chills, insomnia, weakness, urinary retention, paresthesia, serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome toxic epidermal necrolysis, and alterations in rate or strength of uterine contractions during labor. DRUG ABUSE AND DEPENDENCE Controlled Substance. TALWIN Nx is a Schedule IV controlled substance. Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of a drug for non-medical purposes, often in combination with other psychoactive substances. Addiction is a disease of repeated drug abuse. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Addiction is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. 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 addiction and is characterized by misuse of the drug for non-medical purposes, and often in combination with other psychoactive substances. There have been some reports of dependence and of withdrawal symptoms with orally administered pentazocine. Patients with a history of drug dependence should be under close supervision while receiving pentazocine orally. There have been rare reports of possible abstinence syndromes in newborns after prolonged use of pentazocine during pregnancy. There have been reports of development of addiction and physical dependence in patients receiving parenteral pentazocine. People with a history of drug abuse or alcohol abuse may have a higher chance of becoming addicted to opioid medicines. Abrupt dose cessation or rapid dose reduction following the extended use of parenteral pentazocine has resulted in withdrawal symptoms such as abdominal cramps, nausea, vomiting, elevated temperature, chills, rhinorrhea, restlessness, anxiety, or lacrimation. In general opioid therapy should not be abruptly discontinued. When the patient no longer requires treatment with Talwin Nx, the drug should be tapered gradually to prevent signs and symptoms of withdrawal in patients who have been receiving opioids for an extended period of time and might have become physically dependent. In prescribing pentazocine for chronic use, the physician should take under consideration that proper assessment of the patient, proper prescribing practices, periodic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to identify and decrease misuse and abuse of opioid drugs. The amount of naloxone present in TALWIN Nx (0.5 mg per tablet) has no action when taken orally and will not interfere with the pharmacologic action of pentazocine. However, this amount of naloxone given by injection has profound antagonistic action to narcotic analgesics. Severe, even lethal, consequences may result from misuse of tablets by injection either alone or in combination with other substances, such as pulmonary emboli, vascular occlusion, ulceration and abscesses, and withdrawal symptoms in narcotic dependent individuals. TALWIN Nx contains an opioid antagonist, naloxone (0.5 mg). Naloxone is inactive when administered orally at this dose, and its inclusion in TALWIN Nx is intended to curb a form of misuse of oral pentazocine. Parenterally, naloxone is an active narcotic antagonist. Thus, TALWIN Nx has a lower potential for parenteral misuse than the previous oral pentazocine formulation TALWIN® 50 (pentazocine hydrochloride tablets, USP). However, it is still subject to patient misuse and abuse by the oral route. TALWIN® Nx is intended for oral use only. Severe, potentially lethal, reactions may result from misuse of TALWIN® Nx by injection either alone or in combination with other substances. (See DRUG ABUSE AND DEPENDENCE section.) OVERDOSAGE Manifestations. The symptoms and clinical signs of pentazocine overdosage may resemble those of morphine or other opioids. They may include somnolence, respiratory depression, hypotension, hypertension, tachycardia, hallucinations, or seizures. Circulatory failure and deepening coma may occur in more severe cases, particularly in patients who have also ingested other CNS depressants such as alcohol, sedative/hypnotics, or antihistamines. Treatment. Adequate measures to maintain ventilation and general circulatory support should be employed. Assisted or controlled ventilation, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Consideration should be given to gastric lavage and gastric aspiration. For respiratory depression due to overdosage or unusual sensitivity to pentazocine, parenteral naloxone is a specific and effective antagonist. Initial doses of 0.4 to 2.0 mg of naloxone are recommended, repeated at 2-3 minute intervals, if needed, up to a total of 10 mg. Anti convulsant therapy may be necessary. DOSAGE AND ADMINISTRATION Adults. The usual initial adult dose is 1 tablet every three or four hours. This may be increased to 2 tablets when needed. Total daily dosage should not exceed 12 tablets. When anti-inflammatory or antipyretic effects are desired in addition to analgesia, aspirin can be administered concomitantly with this product. Pediatric Patients. Since clinical experience in pediatric patients under 12 years of age is limited, administration of this product in this age group is not recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Duration of Therapy. Patients with chronic pain who receive TALWIN Nx orally for prolonged periods have only rarely been reported to experience withdrawal symptoms when administration was abruptly discontinued (see WARNINGS). Tolerance to the analgesic effect of pentazocine has also been reported only rarely. However, there is no long-term experience with the oral administration of TALWIN Nx. HOW SUPPLIED Talwin Nx (pentazocine and naloxone hydrochlorides, USP) is available as yellow, scored, oblong tablets, debossed with a “W” surrounded by a box on one side and “T51” on the other. Each tablet contains pentazocine hydrochloride equivalent to 50 mg base and naloxone hydrochloride equivalent to 0.5 mg base. Bottles of 100 (NDC 0024-1951-04). Store at 25° C (77° F); excursions permitted between 15° - 30° C (59° F to 86° F). Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 Revised November 2007 ©2007 sanofi-aventis U.S. LLC This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:56.065503	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018733s014lbl.pdf', 'application_number': 18733, 'submission_type': 'SUPPL ', 'submission_number': 14}
11,311	Rx only Exelderm (sulconazole nitrate) Cream, 1.0% For topical use only. Not for ophthalmic use. DESCRIPTION EXELDERM (sulconazole nitrate) CREAM, 1.0% is a broad-spectrum antifungal agent intended for topical application. Sulconazole nitrate, the active ingredient in EXELDERM CREAM, is an imidazole derivative with in vitro antifungal and antiyeast activity. Its chemical name is (+)-1-[2.4-dichloro-β- [(p-chlorobenzyl)-thio]-phenethyl] imidazole mononitrate and it has the following chemical structure: Sulconazole nitrate is a white to off-white crystalline powder with a molecular weight of 460.77. It is freely soluble in pyridine: slightly soluble in ethanol, acetone, and chloroform: and very slightly soluble in water. It has a melting point of about 130°C. EXELDERM CREAM contains sulconazole nitrate 10 mg/g in an emollient cream base consisting of propylene glycol, stearyl alcohol, isopropyl myristate, cetyl alcohol, polysorbate 60, sorbitan monostearate, glyceryl stearate (and) PEG-100 stearate, ascorbyl palmitate, and purified water, with sodium hydroxide and/or nitric acid added to adjust the pH. CLINICAL PHARMACOLOGY Sulconazole nitrate is an imidazole derivative with broad-spectrum antifungal activity that inhibits the growth in vitro of the common pathogenic dermatophytes including Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum and Microsporum canis. It also inhibits (in vitro) the organism responsible for tinea versicolor, Malassezia furfur. Sulconazole nitrate has been shown to be active in vitro against the following microorganisms, although clinical efficacy has not been established: Candida albicans and certain gram positive bacteria. A modified Draize test showed no allergic contact dermatitis and a phototoxicity study showed no phototoxic or photoallergic reaction to sulconazole nitrate cream. Maximization tests with sulconazole nitrate cream showed no evidence of contact sensitization or irritation. INDICATIONS AND USAGE EXELDERM (sulconazole nitrate) CREAM, 1.0% is an antifungal agent indicated for the treatment of tinea pedis (athlete’s foot), tinea cruris, and tinea corporis caused by Trichophyton rubrum, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis,* and for the treatment of tinea versicolor. *Efficacy for this organism in the organ system was studied in fewer than ten infections. CONTRAINDICATIONS EXELDERM (sulconazole nitrate) CREAM, 1.0% is contraindicated in patients who have a history of hypersensitivity to any of its ingredients. PRECAUTIONS General EXELDERM (sulconazole nitrate) CREAM, 1.0% is for external use only. Avoid contact with the eyes. If irritation develops, the cream should be discontinued and appropriate therapy instituted. Information for Patients Patients should be told to use EXELDERM CREAM as directed by the physician, to use it externally only, and to avoid contact with the eyes. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies to determine carcinogenic potential have not been performed. In vitro studies have shown no mutagenic activity. Pregnancy (Category C) There are no adequate and well controlled studies in pregnant women. Sulconazole nitrate should be used during pregnancy only if clearly needed. Sulconazole nitrate has been shown to be embryotoxic in rats when given in doses of 125 times the adult human dose (in mg/kg). The drug was not teratogenic in rats or rabbits at oral doses of 50 mg/kg/day. Sulconazole nitrate given orally to rats at a dose 125 times the human dose resulted in prolonged gestation and dystocia. Several females died during the prenatal period, most likely due to labor complications. Nursing Mothers It is not known whether sulconazole nitrate is excreted in human milk. Caution should be exercised when sulconazole nitrate is administered to a nursing woman. Pediatric Use Safety and effectiveness in children have not been established. Geriatric Use Clinical studies of EXELDERM CREAM, 1.0%, did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and 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 There were no systemic effects and only infrequent cutaneous adverse reactions in 1185 patients treated with sulconazole nitrate cream in controlled clinical trials. Approximately 3% of these patients reported itching, 3% burning or stinging, and 1% redness. These complaints did not usually interfere with treatment. CLINICAL STUDIES In a vehicle-controlled study for the treatment of tinea pedis (moccasin type) due to T. rubrum, after 4- 6 weeks of treatment 69% of patients on the active drug and 19% of patients on the drug vehicle had become KOH and culture negative. In addition, 68% of patients on the active drug and 20% of patients on the drug vehicle showed a good or excellent clinical response. DOSAGE AND ADMINISTRATION A small amount of cream should be gently massaged into the affected and surrounding skin areas once or twice daily, except in tinea pedis, where administration should be twice daily. Early relief of symptoms is experienced by the majority of patients and clinical improvement may be seen fairly soon after treatment is begun; however, tinea corporis/cruris and tinea versicolor should be treated for 3 weeks and tinea pedis for 4 weeks to reduce the possibility of recurrence. If significant clinical improvement is not seen after 4 to 6 weeks of treatment, an alternate diagnosis should be considered. HOW SUPPLIED EXELDERM (sulconazole nitrate) CREAM, 1.0%: 15 g tube - NDC 0072-8200-15 30 g tube - NDC 0072-8200-30 60 g tube - NDC 0072-8200-60 Avoid excessive heat, above 40°C (104°F). 1989,199O WESTWOOD-SQUIBB PHARMACEUTICALS INC., Buffalo, N.Y., U.S.A. 14213 A Bristol-Myers Squibb Company U.S. Patent No. 4.055,652 Developed by Syntex Revised 5/29/03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:56.133416	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18737slr003_exelderm_lbl.pdf', 'application_number': 18737, 'submission_type': 'SUPPL ', 'submission_number': 3}
11,313	Exelderm® (sulconazole nitrate) Solution, 1.0% For topical use only. Not for ophthalmic use. DESCRIPTION EXELDERM (sulconazole nitrate) SOLUTION, 1.0% is a broad-spectrum antifungal agent intended for topical application. Sulconazole nitrate, the active ingredient in EXELDERM SOLUTION, is an imidazole derivative with antifungal and antiyeast activity. Its chemical name is (±)-1-[2,4-Dichloro-β [( p-chlorobenzyl)thio]phenethyl] imidazole mononitrate and it has the following chemical structure: Chemical Structure Sulconazole nitrate is a white to off-white crystalline powder with a molecular weight of 460.77. It is freely soluble in pyridine; slightly soluble in ethanol, acetone, and chloroform; and very slightly soluble in water. It has a melting point of about 130°C. EXELDERM SOLUTION contains sulconazole nitrate 10 mg/mL in a solution of propylene glycol, poloxamer 407, polysorbate 20, butylated hydroxyanisole, and purified water, with sodium hydroxide and, if necessary, nitric acid added to adjust the pH. CLINICAL PHARMACOLOGY Sulconazole nitrate is an imidazole derivative that inhibits the growth of the common pathogenic dermatophytes including Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis. It also inhibits the organism responsible for tinea versicolor, Malassezia furfur, and certain gram positive bacteria. A maximization test with sulconazole nitrate solution showed no evidence of irritation or contact sensitization. INDICATIONS AND USAGE EXELDERM (sulconazole nitrate) SOLUTION, 1.0% is a broad-spectrum antifungal agent indicated for the treatment of tinea cruris and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; and for the treatment of tinea versicolor. Effectiveness has not been proven in tinea pedis (athlete’s foot). Symptomatic relief usually occurs within a few days after starting EXELDERM SOLUTION and clinical improvement usually occurs within one week. CONTRAINDICATIONS EXELDERM (sulconazole nitrate) SOLUTION, 1.0% is contraindicated in patients who have a history of hypersensitivity to any of the ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-738/S-009 Page 2 PRECAUTIONS General EXELDERM (sulconazole nitrate) SOLUTION, 1.0% is for external use only. Avoid contact with the eyes. If irritation develops, the solution should be discontinued and appropriate therapy instituted. Information for Patients Patients should be told to use EXELDERM SOLUTION as directed by the physician, to use it externally only, and to avoid contact with the eyes. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies to determine carcinogenic potential have not been performed. In vitro studies have shown no mutagenic activity. Pregnancy Pregnancy Category C Sulconazole nitrate has been shown to be embryotoxic in rats when given in doses 125 times the human dose (in mg/kg). The drug at this dose given orally to rats also resulted in prolonged gestation and dystocia. Several females died during the perinatal period, most likely due to labor complications. Sulconazole nitrate was not teratogenic in rats or rabbits at oral doses of 50 mg/kg/day. There are no adequate and well-controlled studies in pregnant women. Sulconazole nitrate 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 sulconazole nitrate is administered to a nursing woman. Pediatric Use Safety and effectiveness in children have not been established. Geriatric Use Clinical studies of EXELDERM SOLUTION, 1.0%, did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. ADVERSE REACTIONS There were no systemic effects and only infrequent cutaneous adverse reactions in 370 patients treated with sulconazole nitrate solution in controlled clinical trials. Approximately 1% of these patients reported itching and 1% burning or stinging. These complaints did not usually interfere with treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-738/S-009 Page 3 DOSAGE AND ADMINISTRATION A small amount of the solution should be gently massaged into the affected and surrounding skin areas once or twice daily. Symptomatic relief usually occurs within a few days after starting EXELDERM (sulconazole nitrate) SOLUTION, 1.0%, and clinical improvement usually occurs within one week. To reduce the possibility of recurrence, tinea cruris, tinea corporis, and tinea versicolor should be treated for 3 weeks. If significant clinical improvement is not seen after 4 weeks of treatment, an alternate diagnosis should be considered. HOW SUPPLIED EXELDERM SOLUTION, 1.0% 5 mL Plastic Bottle NDC 10631-100-32 (Physician Sample Not for Sale) 30 mL Plastic Bottle NDC 10631-100-30 Avoid excessive heat, above 40°C (104°F), and protect from light. U. S. Patent No. 4,055,652 Developed by Syntex RANBAXY Jacksonville, FL 32257 USA Revised February 2009 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:56.155368	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018738s009lbl.pdf', 'application_number': 18738, 'submission_type': 'SUPPL ', 'submission_number': 9}
11,312	Rx only Exelderm (sulconazole nitrate) Cream, 1.0% For topical use only. Not for ophthalmic use. DESCRIPTION EXELDERM (sulconazole nitrate) CREAM, 1.0% is a broad-spectrum antifungal agent intended for topical application. Sulconazole nitrate, the active ingredient in EXELDERM CREAM, is an imidazole derivative with in vitro antifungal and antiyeast activity. Its chemical name is (+)-1-[2.4-dichloro-β- [(p-chlorobenzyl)-thio]-phenethyl] imidazole mononitrate and it has the following chemical structure: Sulconazole nitrate is a white to off-white crystalline powder with a molecular weight of 460.77. It is freely soluble in pyridine: slightly soluble in ethanol, acetone, and chloroform: and very slightly soluble in water. It has a melting point of about 130°C. EXELDERM CREAM contains sulconazole nitrate 10 mg/g in an emollient cream base consisting of propylene glycol, stearyl alcohol, isopropyl myristate, cetyl alcohol, polysorbate 60, sorbitan monostearate, glyceryl stearate (and) PEG-100 stearate, ascorbyl palmitate, and purified water, with sodium hydroxide and/or nitric acid added to adjust the pH. CLINICAL PHARMACOLOGY Sulconazole nitrate is an imidazole derivative with broad-spectrum antifungal activity that inhibits the growth in vitro of the common pathogenic dermatophytes including Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum and Microsporum canis. It also inhibits (in vitro) the organism responsible for tinea versicolor, Malassezia furfur. Sulconazole nitrate has been shown to be active in vitro against the following microorganisms, although clinical efficacy has not been established: Candida albicans and certain gram positive bacteria. A modified Draize test showed no allergic contact dermatitis and a phototoxicity study showed no phototoxic or photoallergic reaction to sulconazole nitrate cream. Maximization tests with sulconazole nitrate cream showed no evidence of contact sensitization or irritation. INDICATIONS AND USAGE EXELDERM (sulconazole nitrate) CREAM, 1.0% is an antifungal agent indicated for the treatment of tinea pedis (athlete’s foot), tinea cruris, and tinea corporis caused by Trichophyton rubrum, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis,* and for the treatment of tinea versicolor. *Efficacy for this organism in the organ system was studied in fewer than ten infections. CONTRAINDICATIONS EXELDERM (sulconazole nitrate) CREAM, 1.0% is contraindicated in patients who have a history of hypersensitivity to any of its ingredients. PRECAUTIONS General EXELDERM (sulconazole nitrate) CREAM, 1.0% is for external use only. Avoid contact with the eyes. If irritation develops, the cream should be discontinued and appropriate therapy instituted. Information for Patients Patients should be told to use EXELDERM CREAM as directed by the physician, to use it externally only, and to avoid contact with the eyes. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies to determine carcinogenic potential have not been performed. In vitro studies have shown no mutagenic activity. Pregnancy (Category C) There are no adequate and well controlled studies in pregnant women. Sulconazole nitrate should be used during pregnancy only if clearly needed. Sulconazole nitrate has been shown to be embryotoxic in rats when given in doses of 125 times the adult human dose (in mg/kg). The drug was not teratogenic in rats or rabbits at oral doses of 50 mg/kg/day. Sulconazole nitrate given orally to rats at a dose 125 times the human dose resulted in prolonged gestation and dystocia. Several females died during the prenatal period, most likely due to labor complications. Nursing Mothers It is not known whether sulconazole nitrate is excreted in human milk. Caution should be exercised when sulconazole nitrate is administered to a nursing woman. Pediatric Use Safety and effectiveness in children have not been established. Geriatric Use Clinical studies of EXELDERM CREAM, 1.0%, did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and 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 There were no systemic effects and only infrequent cutaneous adverse reactions in 1185 patients treated with sulconazole nitrate cream in controlled clinical trials. Approximately 3% of these patients reported itching, 3% burning or stinging, and 1% redness. These complaints did not usually interfere with treatment. CLINICAL STUDIES In a vehicle-controlled study for the treatment of tinea pedis (moccasin type) due to T. rubrum, after 4- 6 weeks of treatment 69% of patients on the active drug and 19% of patients on the drug vehicle had become KOH and culture negative. In addition, 68% of patients on the active drug and 20% of patients on the drug vehicle showed a good or excellent clinical response. DOSAGE AND ADMINISTRATION A small amount of cream should be gently massaged into the affected and surrounding skin areas once or twice daily, except in tinea pedis, where administration should be twice daily. Early relief of symptoms is experienced by the majority of patients and clinical improvement may be seen fairly soon after treatment is begun; however, tinea corporis/cruris and tinea versicolor should be treated for 3 weeks and tinea pedis for 4 weeks to reduce the possibility of recurrence. If significant clinical improvement is not seen after 4 to 6 weeks of treatment, an alternate diagnosis should be considered. HOW SUPPLIED EXELDERM (sulconazole nitrate) CREAM, 1.0%: 15 g tube - NDC 0072-8200-15 30 g tube - NDC 0072-8200-30 60 g tube - NDC 0072-8200-60 Avoid excessive heat, above 40°C (104°F). 1989,199O WESTWOOD-SQUIBB PHARMACEUTICALS INC., Buffalo, N.Y., U.S.A. 14213 A Bristol-Myers Squibb Company U.S. Patent No. 4.055,652 Developed by Syntex Revised 5/29/03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:56.188793	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18737slr003_exelderm_lbl.pdf', 'application_number': 18738, 'submission_type': 'SUPPL ', 'submission_number': 7}
11,314	3 DIPROLENE® 1 brand of augmented betamethasone dipropionate ointment* 2 Ointment 0.05% (potency expressed as betamethasone) 3 *Vehicle augments the penetration of the steroid. 4 For Dermatologic Use Only - 5 Not for Ophthalmic Use 6 DESCRIPTION DIPROLENE® (augmented betamethasone dipropionate ointment) 7 Ointment contains betamethasone dipropionate, USP, a synthetic adrenocorticosteroid, 8 for dermatologic use. Betamethasone, an analog of prednisolone, has a high degree of 9 corticosteroid activity and a slight degree of mineralocorticoid activity. Betamethasone 10 dipropionate is the 17, 21-dipropionate ester of betamethasone. 11 Chemically, betamethasone dipropionate is 9-fluoro-11β, 17,21-trihydroxy-16β 12 -methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, with the empirical formula 13 C28H37FO7., a molecular weight of 504.6 and the following structural formula: 14 It is a white to creamy-white, odorless powder insoluble in water; freely soluble in 15 acetone and in chloroform; sparingly soluble in alcohol. 16 Each gram of DIPROLENE Ointment 0.05% contains 0.643 mg betamethasone 17 dipropionate, USP (equivalent to 0.5 mg betamethasone), in a vehicle of propylene 18 glycol, propylene glycol stearate, white wax, and white petrolatum. 19 CLINICAL PHARMACOLOGY The corticosteroids are a class of compounds 20 comprising steroid hormones secreted by the adrenal cortex and their synthetic 21 analogs. In pharmacologic doses, corticosteroids are used primarily for their anti- 22 inflammatory and/or immunosuppressive effects. Topical corticosteroids, such as 23 betamethasone dipropionate, are effective in the treatment of corticosteroid-responsive 24 dermatoses primarily because of their anti-inflammatory, antipruritic, and 25 vasoconstrictive actions. However, while the physiologic, pharmacologic, and clinical 26 effects of the corticosteroids are well known, the exact mechanisms of their actions in 27 each disease are uncertain. Betamethasone dipropionate, a corticosteroid, has been 28 shown to have topical (dermatologic) and systemic pharmacologic and metabolic effects 29 characteristic of this class of drugs. 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is 31 determined by many factors including the vehicle, the integrity of the epidermal barrier 32 and the use of occlusive dressings. (See DOSAGE AND ADMINISTRATION section.) 33 Topical corticosteroids can be absorbed through normal intact skin. Inflammation and/or 34 other disease processes in the skin may increase percutaneous absorption. Occlusive 35 dressings substantially increase the percutaneous absorption of topical corticosteroids. 36 (See DOSAGE AND ADMINISTRATION section.) 37 Once absorbed through the skin, topical corticosteroids enter pharmacokinetic 38 pathways similar to systemically administered corticosteroids. Corticosteroids are bound 39 to plasma proteins in varying degrees, are metabolized primarily in the liver and 40 excreted by the kidneys. Some of the topical corticosteroids and their metabolites are 41 also excreted into the bile. 42 Studies performed with DIPROLENE Ointment indicate that it is in the super-high range 43 of potency as compared with other topical corticosteroids. 44 INDICATIONS AND USAGE DIPROLENE Ointment is a super-high potency 45 corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of 46 corticosteroid-responsive dermatoses in patients 13 years and older. The total dose 47 should not exceed 50 g per week because of the potential for the drug to suppress the 48 hypothalamic-pituitary-adrenal (HPA) axis. 49 CONTRAINDICATIONS DIPROLENE Ointment is contraindicated in patients who are 50 hypersensitive to betamethasone dipropionate, to other corticosteroids, or to any 51 ingredient in this preparation. 52 PRECAUTIONS General: Systemic absorption of topical corticosteroids has produced 53 reversible HPA axis suppression, manifestations of Cushing's syndrome, 54 hyperglycemia, and glucosuria in some patients. Conditions which augment systemic 55 absorption include the application of the more potent corticosteroids, use over large 56 surface areas, prolonged use, and the addition of occlusive dressings. Use of more than 57 one corticosteroid-containing product at the same time may increase total systemic 58 glucocorticoid exposure. (See DOSAGE AND ADMINISTRATION section.) 59 Therefore, patients receiving a large dose of a potent topical steroid applied to a large 60 surface area should be evaluated periodically for evidence of HPA axis suppression by 61 using the urinary free cortisol and ACTH stimulation tests. . If HPA axis suppression is 62 noted, an attempt should be made to withdraw the drug, to reduce the frequency of 63 application, or to substitute a less potent steroid. 64 Recovery of HPA axis function is generally prompt and complete upon discontinuation 65 of the drug. Patients should not be treated with amounts of DIPROLENE Ointment 66 greater than 50 g per week because of the potential for the drug to suppress HPA axis. 67 Patients receiving super-potent corticosteroids should not be treated for more than 2 68 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 weeks at a time and only small areas should be treated at any one time due to the 69 increased risk of HPA suppression. 70 At 14 g per day DIPROLENE Ointment was shown to depress the plasma levels of 71 adrenal cortical hormones following repeated application to diseased skin in patients 72 with psoriasis. These effects were reversible upon discontinuation of treatment. At 7 g 73 per day DIPROLENE Ointment was shown to cause minimal inhibition of the HPA axis 74 when applied 2 times daily for 2 to 3 weeks in healthy patients and in patients with 75 psoriasis and eczematous disorders. 76 With 6 to 7 g of DIPROLENE Ointment applied once daily for 3 weeks, no significant 77 inhibition of the HPA axis was observed in patients with psoriasis and atopic dermatitis, 78 as measured by plasma cortisol and 24-hour urinary 17-hydroxy-corticosteroid levels. 79 Infrequently, signs and symptoms of steroid withdrawal may occur, requiring 80 supplemental systemic corticosteroids. 81 Pediatric patients may absorb proportionally larger amounts of topical corticosteroids 82 and thus be more susceptible to systemic toxicity. (See PRECAUTIONS - Pediatric 83 Use.) 84 If irritation develops, topical corticosteroids should be discontinued and appropriate 85 therapy instituted. 86 In the presence of dermatological infections, the use of an appropriate antifungal or 87 antibacterial agent should be instituted. If a favorable response does not occur 88 promptly, the corticosteroid should be discontinued until the infection has been 89 adequately controlled. DIPROLENE Ointment should not be used in the treatment of 90 rosacea or perioral dermatitis, and it should not be used on the face, groin, or in the 91 axillae. 92 Information for Patients: Patients using topical corticosteroids should receive the 93 following information and instructions. This information is intended to aid in the safe and 94 effective use of this medication. It is not a disclosure of all possible adverse or intended 95 effects. 96 l. This medication is to be used as directed by the physician and should not be used 97 longer than the prescribed time period. It is for external use only. Avoid contact with 98 the eyes. 99 2. This medication should not be used for any disorder other than that for which it was 100 prescribed. 101 3. The treated skin area should not be bandaged, otherwise covered or wrapped, so as 102 to be occlusive (See DOSAGE AND ADMINISTRATION section). 4. Patients 103 should report to their physician any signs of local adverse reactions. 104 5. Patients should be advised not to use DIPROLENE Ointment in the treatment of 105 diaper dermatitis. DIPROLENE Ointment should not be applied in the diaper areas 106 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 as diapers or plastic pants may constitute occlusive dressing (See DOSAGE AND 107 ADMINISTRATION). 108 6. This medication should not be used on the face, underarms, or groin areas unless 109 directed by the physician. 110 7. As with other corticosteroids, therapy should be discontinued when control is 111 achieved. If no improvement is seen within 2 weeks, contact the physician. 112 8. Other corticosteroid-containing products should not be used with Diprolene 113 Ointment. 114 Laboratory Tests: The following tests may be helpful in evaluating patients for HPA 115 axis suppression: 116 ACTH stimulation test 117 Urinary free cortisol test 118 Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term animal 119 studies have not been performed to evaluate the carcinogenic potential of 120 betamethasone dipropionate. Betamethasone was negative in the bacterial 121 mutagenicity assay (Salmonella typhimurium and Escherichia coli), and in the 122 mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in-vitro, 123 human lymphocyte chromosome aberration assay, and equivocal in the in-vivo mouse 124 bone marrow micronucleus assay. This pattern of response is similar to that of 125 dexamethasone and hydrocortisone. Studies in rabbits, mice and rats using 126 intramuscular doses up to 1, 33 and 2 mg/kg, respectively, resulted in dose related 127 increases in fetal resorptions in rabbits and mice. 128 Pregnancy: Teratogenic effects: Pregnancy category C. Corticosteroids have been 129 shown to be teratogenic in laboratory animals when administered systemically at 130 relatively low dosage levels. Some corticosteroids have been shown to be teratogenic 131 after dermal application in laboratory animals. Betamethasone dipropionate has been 132 shown to be teratogenic in rabbits when given by the intramuscular route at doses of 133 0.05 mg/kg. This dose is approximately 0.2 times the human topical dose of 134 DIPROLENE Ointment in mg/m2 of body surface area, assuming 100% absorption and 135 the use in a 60 kg person of 7 g per day. The abnormalities observed included umbilical 136 hernias, cephalocele and cleft palate. There are no adequate and well-controlled 137 studies in pregnant women on teratogenic effects from topically applied corticosteroids. 138 DIPROLENE Ointment should be used during pregnancy only if the potential benefit 139 justifies the potential risk to the fetus. 140 Nursing Mothers: Systemically administered corticosteroids appear in human milk and 141 could suppress growth, interfere with endogenous corticosteroid production, or cause 142 other untoward effects. It is not known whether topical administration of corticosteroids 143 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 could result in sufficient systemic absorption to produce detectable quantities in human 144 milk. Because many drugs are excreted in human milk, caution should be exercised 145 when DIPROLENE Ointment is administered to a nursing woman. 146 Pediatric Use: Use of DIPROLENE Ointment, 0.05%, in pediatric patients 12 years of 147 age and younger is not recommended. (See CLINICAL PHARMACOLOGY and 148 ADVERSE REACTIONS sections.) 149 Pediatric patients may demonstrate greater susceptibility to topical corticosteroid- 150 induced HPA axis suppression and Cushing's syndrome than mature patients because 151 of a larger skin surface area to body weight ratio. 152 Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and 153 intracranial hypertension have been reported in children receiving topical 154 corticosteroids. Manifestations of adrenal suppression in children include linear growth 155 retardation, delayed weight gain, low plasma cortisol levels and an absence of response 156 to ACTH stimulation. Manifestations of intracranial hypertension include bulging 157 fontanelles, headaches, and bilateral papilledema. Chronic corticosteroid therapy may 158 interfere with the growth and development of children. 159 ADVERSE REACTIONS The local adverse reactions which were reported with 160 DIPROLENE Ointment during controlled clinical trials were as follows: erythema, 161 folliculitis, pruritus and vesiculation each occurring in less than 1% of patients. 162 The following additional local adverse reactions have been reported with topical 163 corticosteroids, and they may occur more frequently with the use of occlusive dressings 164 and higher potency corticosteroids. These reactions are listed in an approximately 165 decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, 166 hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic 167 contact dermatitis, secondary infection, skin atrophy, striae and miliaria. 168 Systemic absorption of topical corticosteroids has produced reversible hypothalamic- 169 pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, 170 hyperglycemia, and glucosuria in some patients. 171 OVERDOSAGE Topically applied DIPROLENE Ointment can be absorbed in sufficient 172 amounts to produce systemic effects (See PRECAUTIONS). 173 DOSAGE AND ADMINISTRATION Apply a thin film of DIPROLENE Ointment to the 174 affected skin once or twice daily. DIPROLENE Ointment is a super-high potency topical 175 corticosteroid. Treatment with DIPROLENE Ointment should be limited to 50 g per 176 week. 177 As with other corticosteroids, therapy should be discontinued when control is achieved. 178 If no improvement is seen within 2 weeks, reassessment of diagnosis may be 179 necessary. 180 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 DIPROLENE Ointment should not be used with occlusive dressings. Diprolene 181 Ointment should not be applied to the diaper area if the patient requires diapers or 182 plastic pants as these garments may constitute occlusive dressing. 183 HOW SUPPLIED DIPROLENE Ointment 0.05 % is supplied in 15 g (NDC 184 0085-0575-02), and 50 g (NDC 0085-0575-05) tubes; boxes of one. 185 Store between 2° and 25°C (36° and 77°F). 186 Schering Corporation 187 Kenilworth, NJ 07033 USA 188 Copyright© 1983, 1992, 1997, 1999, 2004 Schering Corporation 189 All rights reserved. 190 Rev. 2/05 191 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/ --------------------- Stanka Kukich 10/7/2005 11:54:20 AM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:56.397863	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018741s016lbl.pdf', 'application_number': 18741, 'submission_type': 'SUPPL ', 'submission_number': 16}
11,316	SPECTAZOLE (econazole nitrate 1%) Cream 631-11-331-1 For Topical Use Only DESCRIPTION: SPECTAZOLE Cream contains the antifungal agent, econazole nitrate 1%, in a water-miscible base consisting of pegoxol 7 stearate, peglicol 5 oleate, mineral oil, benzoic acid, butylated hydroxyanisole, and purified water. The white to off-white soft cream is for topical use only. Chemically, econazole nitrate is 1-[2-{(4-chloro-phenyl) methoxy}-2-(2,4-dichlorophenyl)ethyl] 1H-imidazole mononitrate. Its structure is as follows: structural formula CLINICAL PHARMACOLOGY: After topical application to the skin of normal subjects, systemic absorption of econazole nitrate is extremely low. Although most of the applied drug remains on the skin surface, drug concentrations were found in the stratum corneum which, by far, exceeded the minimum inhibitory concentration for dermatophytes. Inhibitory concentrations were achieved in the epidermis and as deep as the middle region of the dermis. Less than 1% of the applied dose was recovered in the urine and feces. Microbiology: Econazole nitrate has 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. Dermatophytes Yeasts Epidermophyton floccosum Trichophyton mentagrophytes Candida albicans Microsporum audouini Trichophyton rubrum Malassezia furfur Microsporum canis Trichophyton tonsurans Microsporum gypseum Econazole nitrate exhibits broad-spectrum antifungal activity against the following organisms in vitro, but the clinical significance of these data is unknown. Dermatophytes Yeasts Trichophyton verrucosum Candida guillermondii Candida parapsilosis Candida tropicalis Reference ID: 3479065 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE: SPECTAZOLE Cream is indicated for topical application in the treatment of tinea pedis, tinea cruris, and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Microsporum canis, Microsporum audouini, Microsporum gypseum, and Epidermophyton floccosum, in the treatment of cutaneous candidiasis, and in the treatment of tinea versicolor. CONTRAINDICATIONS: SPECTAZOLE Cream is contraindicated in individuals who have shown hypersensitivity to any of its ingredients. WARNINGS: SPECTAZOLE is not for ophthalmic use. PRECAUTIONS: General: If a reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued. For external use only. Avoid introduction of SPECTAZOLE Cream into the eyes. Drug Interactions: Warfarin: Concomitant administration of econazole and warfarin has resulted in enhancement of anticoagulation effect. Most cases reported product application with use under occlusion, genital application, or application to large body surface area which may increase the systemic absorption of econzole nitrate. Monitoring of International Normalized Ratio (INR) and/or prothrombin time may be indicated especially for patients who apply econazole to large body surface areas, in the genital area, or under occlusion. Carcinogenicity Studies: Long-term animal studies to determine carcinogenic potential have not been performed. Fertility (Reproduction): Oral administration of econazole nitrate in rats has been reported to produce prolonged gestation. Intravaginal administration in humans has not shown prolonged gestation or other adverse reproductive effects attributable to econazole nitrate therapy. Pregnancy: Pregnancy Category C. Econazole nitrate has not been shown to be teratogenic when administered orally to mice, rabbits or rats. Fetotoxic or embryotoxic effects were observed in Segment I oral studies with rats receiving 10 to 40 times the human dermal dose. Similar effects were observed in Segment II or Segment III studies with mice, rabbits and/or rats receiving oral doses 80 or 40 times the human dermal dose. Econazole nitrate should be used in the first trimester of pregnancy only when the physician considers it essential to the welfare of the patient. The drug should be used during the second and third trimesters of pregnancy only if clearly needed. Nursing Mothers: It is not known whether econazole nitrate is excreted in human milk. Following oral administration of econazole nitrate to lactating rats, econazole and/or metabolites were excreted in milk and were found in nursing pups. Also, in lactating rats receiving large oral doses (40 or 80 times the human dermal dose), there was a reduction in post partum viability of pups and survival to weaning; however, at these high doses, maternal toxicity was present and may have been a contributing factor. Caution should be exercised when econazole nitrate is administered to a nursing woman. Reference ID: 3479065 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS: During clinical trials, approximately 3% of patients treated with econazole nitrate 1% cream reported side effects thought possibly to be due to the drug, consisting mainly of burning, itching, stinging, and erythema. One case of pruritic rash has also been reported. OVERDOSE: Overdosage of econazole nitrate in humans has not been reported to date. In mice, rats, guinea pigs and dogs, the oral LD 50 values were found to be 462, 668, 272, and >160 mg/kg, respectively. DOSAGE AND ADMINISTRATION: Sufficient SPECTAZOLE Cream should be applied to cover affected areas once daily in patients with tinea pedis, tinea cruris, tinea corporis, and tinea versicolor, and twice daily (morning and evening) in patients with cutaneous candidiasis. Early relief of symptoms is experienced by the majority of patients and clinical improvement may be seen fairly soon after treatment is begun; however, candidal infections and tinea cruris and corporis should be treated for two weeks and tinea pedis for one month in order to reduce the possibility of recurrence. If a patient shows no clinical improvement after the treatment period, the diagnosis should be redetermined. Patients with tinea versicolor usually exhibit clinical and mycological clearing after two weeks of treatment. HOW SUPPLIED: SPECTAZOLE (econazole nitrate 1%) Cream is supplied in tubes of 15 grams (NDC 0259-5460-02), 30 grams (NDC 0259-5460-01), and 85 grams (NDC 0259-5460-03). Store SPECTAZOLE Cream below 86°F. Merz Pharmaceuticals, LLC Greensboro, NC 27410 Printed in U.S.A Revised February 2014 631-11-331-1 Reference ID: 3479065 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:56.452833	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018751s023lbledt.pdf', 'application_number': 18751, 'submission_type': 'SUPPL ', 'submission_number': 23}
11,315	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	2025-02-12T13:44:56.549729	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18748slr010_loprox_lbl.pdf', 'application_number': 18748, 'submission_type': 'SUPPL ', 'submission_number': 10}
11,317	TENORETIC® (atenolol and chlorthalidone) DESCRIPTION TENORETIC® (atenolol and chlorthalidone) is for the treatment of hypertension. It combines the antihypertensive activity of two agents: a beta1-selective (cardioselective) hydrophilic blocking agent (atenolol, TENORMIN®) and a monosulfonamyl diuretic (chlorthalidone). Atenolol is Benzeneacetamide, 4-[2'-hydroxy-3'-[(1-methylethyl) amino] propoxy]-. structural formula C14H22N2O3 Atenolol (free base) is a relatively polar hydrophilic compound with a water solubility of 26.5 mg/mL at 37° C. It is freely soluble in 1N HCl (300 mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at 25°C). Chlorthalidone is 2-Chloro-5-(1-hydroxy-3-oxo-1 isoindolinyl) benzene sulfonamide: structural formula C14H11CIN2O4S Chlorthalidone has a water solubility of 12 mg/100 mL at 20°C. Each TENORETIC 100 Tablet contains: Atenolol (TENORMIN®).......................................100 mg Chlorthalidone........................................................ 25 mg Each TENORETIC 50 Tablet contains: Reference ID: 3001215 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Atenolol (TENORMIN®).........................................50 mg Chlorthalidone..........................................................25 mg Inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. CLINICAL PHARMACOLOGY Tenoretic Atenolol and chlorthalidone have been used singly and concomitantly for the treatment of hypertension. The antihypertensive effects of these agents are additive, and studies have shown that there is no interference with bioavailability when these agents are given together in the single combination tablet. Therefore, this combination provides a convenient formulation for the concomitant administration of these two entities. In patients with more severe hypertension, TENORETIC may be administered with other antihypertensives such as vasodilators. Atenolol: Atenolol is a beta1-selective (cardioselective) beta-adrenergic receptor blocking agent without membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities. This preferential effect is not absolute, however, and at higher doses, atenolol inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Pharmacodynamics In standard animal or human pharmacological tests, beta-adrenoreceptor blocking activity of atenolol has been demonstrated by: (1) reduction in resting and exercise heart rates and cardiac output, (2) reduction of systolic and diastolic blood pressure at rest and on exercise, (3) inhibition of isoproterenol induced tachycardia and (4) reduction in reflex orthostatic tachycardia. A significant beta-blocking effect of atenolol, as measured by reduction of exercise tachycardia, is apparent within one hour following oral administration of a single dose. This effect is maximal at about 2 to 4 hours and persists for at least 24 hours. The effect at 24 hours is dose related and also bears a linear relationship to the logarithm of plasma atenolol concentration. However, as has been shown for all beta blocking agents, the antihypertensive effect does not appear to be related to plasma level. Reference ID: 3001215 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In normal subjects, the beta1-selectivity of atenolol has been shown by its reduced ability to reverse the beta2-mediated vasodilating effect of isoproterenol as compared to equivalent beta-blocking doses of propranolol. In asthmatic patients, a dose of atenolol producing a greater effect on resting heart rate than propranolol resulted in much less increase in airway resistance. In a placebo controlled comparison of approximately equipotent oral doses of several beta blockers, atenolol produced a significantly smaller decrease of FEV1 than nonselective beta blockers, such as propranolol and unlike those agents did not inhibit bronchodilation in response to isoproterenol. Consistent with its negative chronotropic effect due to beta blockade of the SA node, atenolol increases sinus cycle length and sinus node recovery time. Conduction in the AV node is also prolonged. Atenolol is devoid of membrane stabilizing activity, and increasing the dose well beyond that producing beta blockade does not further depress myocardial contractility. Several studies have demonstrated a moderate (approximately 10%) increase in stroke volume at rest and exercise. In controlled clinical trials, atenolol given as a single daily dose, was an effective antihypertensive agent providing 24-hour reduction of blood pressure. Atenolol has been studied in combination with thiazide-type diuretics and the blood pressure effects of the combination are approximately additive. Atenolol is also compatible with methyldopa, hydralazine and prazosin, the combination resulting in a larger fall in blood pressure than with the single agents. The dose range of atenolol is narrow, and increasing the dose beyond 100 mg once daily is not associated with increased antihypertensive effect. The mechanisms of the antihypertensive effects of beta-blocking agents have not been established. Several mechanisms have been proposed and include: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output, (2) a central effect leading to reduced sympathetic outflow to the periphery and (3) suppression of renin activity. The results from long-term studies have not shown any diminution of the antihypertensive efficacy of atenolol with prolonged use. 3 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics and Metabolism In man, absorption of an oral dose is rapid and consistent but incomplete. Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, the remainder being excreted unchanged in the feces. Peak blood levels are reached between 2 and 4 hours after ingestion. Unlike propranolol or metoprolol, but like nadolol, hydrophilic atenolol undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion. Atenolol also differs from propranolol in that only a small amount (6 - 16%) is bound to proteins in the plasma. This kinetic profile results in relatively consistent plasma drug levels with about a fourfold interpatient variation. There is no information as to the pharmacokinetic effect of atenolol on chlorthalidone. The elimination half-life of atenolol is approximately 6 to 7 hours and there is no alteration of the kinetic profile of the drug by chronic administration. Following doses of 50 mg or 100 mg, both beta-blocking and antihypertensive effects persist for at least 24 hours. When renal function is impaired, elimination of atenolol is closely related to the glomerular filtration rate; but significant accumulation does not occur until the creatinine clearance falls below 35 mL/min/1.73m2 (see prescribing information for atenolol [TENORMIN®]). Atenolol Geriatric Pharmacology In general, elderly patients present higher atenolol plasma levels with total clearance values about 50% lower than younger subjects. The half-life is markedly longer in the elderly compared to younger subjects. The reduction of atenolol clearance follows the general trend that the elimination of renally excreted drugs is decreased with increasing age. 4 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chlorthalidone: Chlorthalidone is a monosulfonamyl diuretic which differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is an oral diuretic with prolonged action and low toxicity. The diuretic effect of the drug occurs within 2 hours of an oral dose. It produces diuresis with greatly increased excretion of sodium and chloride. At maximal therapeutic dosage, chlorthalidone is approximately equal in its diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics. The site of action appears to be the cortical diluting segment of the ascending limb of Henle's loop of the nephron. INDICATIONS AND USAGE TENORETIC is indicated in the treatment of hypertension. This fixed dose combination drug is not indicated for initial therapy of hypertension. If the fixed dose combination represents the dose appropriate to the individual patient's needs, it may be more convenient than the separate components. CONTRAINDICATIONS TENORETIC is contraindicated in patients with: sinus bradycardia; heart block greater than first degree; cardiogenic shock; overt cardiac failure (see WARNINGS); anuria; hypersensitivity to this product or to sulfonamide-derived drugs. WARNINGS Cardiac Failure Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. IN PATIENTS WITHOUT A HISTORY OF CARDIAC FAILURE, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately according to currently recommended guidelines, and the response observed closely. If cardiac failure continues despite adequate treatment, TENORETIC should be withdrawn. (See DOSAGE AND ADMINISTRATION.) 5 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal and Hepatic Disease and Electrolyte Disturbances Since atenolol is excreted via the kidneys, TENORETIC should be used with caution in patients with impaired renal function. In patients with renal disease, thiazides may precipitate azotemia. Since cumulative effects may develop in the presence of impaired renal function, if progressive renal impairment becomes evident, TENORETIC should be discontinued. In patients with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. TENORETIC should be used with caution in these patients. Ischemic Heart Disease Following abrupt cessation of therapy with certain beta-blocking agents in patients with coronary artery disease, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported. Therefore, such patients should be cautioned against interruption of therapy without the physician's advice. Even in the absence of overt angina pectoris, when discontinuation of TENORETIC is planned, the patient should be carefully observed and should be advised to limit physical activity to a minimum. TENORETIC should be reinstated if withdrawal symptoms occur. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue TENORETIC therapy abruptly even in patients treated only for hypertension. Concomitant Use of Calcium Channel Blockers Bradycardia and heart block can occur and the left ventricular end diastolic pressure can rise when beta-blockers are administered with verapamil or diltiazem. Patients with pre existing conduction abnormalities or left ventricular dysfunction are particularly susceptible. (See PRECAUTIONS.) 6 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Bronchospastic Diseases PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta1-selectivity, however, TENORETIC may be used with caution in patients with bronchospastic disease who do not respond to or cannot tolerate, other antihypertensive treatment. Since beta1-selectivity is not absolute, the lowest possible dose of TENORETIC should be used and a beta2-stimulating agent (bronchodilator) should be made available. If dosage must be increased, dividing the dose should be considered in order to achieve lower peak blood levels. 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. Metabolic and Endocrine Effects TENORETIC may be used with caution in diabetic patients. Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. At recommended doses atenolol does not potentiate insulin-induced hypoglycemia and, unlike nonselective beta blockers, does not delay recovery of blood glucose to normal levels. Insulin requirements in diabetic patients may be increased, decreased or unchanged; latent diabetes mellitus may become manifest during chlorthalidone administration. Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom TENORETIC therapy is to be withdrawn should be monitored closely. 7 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Because calcium excretion is decreased by thiazides, TENORETIC should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy; however, the common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen. Hyperuricemia may occur, or acute gout may be precipitated in certain patients receiving thiazide therapy. Untreated Pheochromocytoma TENORETIC should not be given to patients with untreated pheochromocytoma. Pregnancy and Fetal Injury Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the placental barrier and appears in cord blood. Administration of atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age. No studies have been performed on the use of atenolol in the first trimester and the possibility of fetal injury cannot be excluded. 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. Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORETIC is administered during pregnancy or to a woman who is breast-feeding. (See PRECAUTIONS, Nursing Mothers.) 8 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TENORETIC was studied for teratogenic potential in the rat and rabbit. Doses of atenolol/chlorthalidone of 8/2, 80/20, and 240/60 mg/kg/day were administered orally to pregnant rats with no evidence of embryofetotoxicity observed. Two studies were conducted in rabbits. In the first study, pregnant rabbits were dosed with 8/2, 80/20, and 160/40 mg/kg/day of atenolol/chlorthalidone. No teratogenic effects were noted, but embryonic resorptions were observed at all dose levels (ranging from approximately 5 times to 100 times the maximum recommended human dose). In the second rabbit study, doses of atenolol/chlorthalidone were 4/1, 8/2, and 20/5 mg/kg/day. No teratogenic or embryotoxic effects were demonstrated. Atenolol Atenolol has been shown to produce a dose-related increase in embryo/fetal resorptions in rats at doses equal to or greater than 50 mg/kg/day or 25 or more times the maximum recommended human antihypertensive dose. Although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg/day or 12.5 times the maximum recommended human antihypertensive dose.* Chlorthalidone Thiazides cross the placental barrier and appear in cord blood. The use of chlorthalidone and related drugs in pregnant women requires that the anticipated benefits of the drug be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult. Based on the maximum dose of 100 mg/day in a 50 kg patient. PRECAUTIONS General TENORETIC may aggravate peripheral arterial circulatory disorders. 9 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Electrolyte and Fluid Balance Status Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Patients should be observed for clinical signs of fluid or electrolyte imbalance; i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Measurement of potassium levels is appropriate especially in elderly patients, those receiving digitalis preparations for cardiac failure, patients whose dietary intake of potassium is abnormally low, or those suffering from gastrointestinal complaints. Hypokalemia may develop especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids or ACTH. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (eg, increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high potassium content. Any chloride deficit during thiazide therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice. 10 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions TENORETIC may potentiate the action of other antihypertensive agents used concomitantly. Patients treated with TENORETIC plus a catecholamine depletor (eg, reserpine) should be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope or postural hypotension. Calcium channel blockers may also have an additive effect when given with TENORETIC. (See WARNINGS.) Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects. Disopyramide has been associated with severe bradycardia, asystole and heart failure when administered with beta blockers. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta blockers. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude the therapeutic effectiveness of norepinephrine. Thiazides may increase the responsiveness to tubocurarine. Concomitant use of prostaglandin synthase inhibiting drugs, eg, indomethacin, may decrease the hypotensive effects of beta blockers. Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such preparations with TENORETIC. Beta blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta blocker should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta blockers should be delayed for several days after clonidine administration has stopped. 11 Reference ID: 3001215 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 anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Other Precautions In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. The possible exacerbation or activation of systemic lupus erythematosus has been reported. The antihypertensive effects of thiazides may be enhanced in the postsympathectomy patient. Carcinogenesis, Mutagenesis, Impairment of Fertility Two long-term (maximum dosing duration of 18 or 24 months) rat studies and one long-term (maximum dosing duration of 18 months) mouse study, each employing dose levels as high as 300 mg/kg/day or 150 times the maximum recommended human antihypertensive dose, did not indicate a carcinogenic potential of atenolol. A third (24 month) rat study, employing doses of 500 and 1,500 mg/kg/day (250 and 750 times the maximum recommended human antihypertensive dose) resulted in increased incidences of benign adrenal medullary tumors in males and females, mammary fibroadenomas in females, and anterior pituitary adenomas and thyroid parafollicular cell carcinomas in males. No evidence of a mutagenic potential of atenolol was Based on the maximum dose of 100 mg/day in a 50 kg patient. 12 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda uncovered in the dominant lethal test (mouse), in vivo cytogenetics test (Chinese hamster) or Ames test (S typhimurium). Fertility of male or female rats (evaluated at dose levels as high as 200 mg/kg/day or 100 times the maximum recommended human dose) was unaffected by atenolol administration. Animal Toxicology Six month oral administration studies were conducted in rats and dogs using TENORETIC doses up to 12.5 mg/kg/day (atenolol/chlorthalidone 10/2.5 mg/kg/day -- approximately five times the maximum recommended human antihypertensive dose). There were no functional or morphological abnormalities resulting from dosing either compound alone or together other than minor changes in heart rate, blood pressure and urine chemistry which were attributed to the known pharmacologic properties of atenolol and/or chlorthalidone. Chronic studies of atenolol performed in animals have revealed the occurrence of vacuolation of epithelial cells of Brunner's glands in the duodenum of both male and female dogs at all tested dose levels (starting at 15 mg/kg/day or 7.5 times the maximum recommended human antihypertensive dose) and increased incidence of atrial degeneration of hearts of male rats at 300 but not 150 mg atenolol/kg/day (150 and 75 times the maximum recommended human antihypertensive dose, respectively). Use in Pregnancy Pregnancy Category D: See WARNINGS - Pregnancy and Fetal Injury. Nursing Mothers Atenolol is excreted in human breast milk at a ratio of 1.5 to 6.8 when compared to the concentration in plasma. Caution should be exercised when atenolol is administered to a nursing woman. Clinically significant bradycardia has been reported *Based on the maximum dose of 100 mg/day in a 50 kg patient. Reference ID: 3001215 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda in breast-fed infants. Premature infants, or infants with impaired renal function, may be more likely to develop adverse effects. Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORETIC is administered during pregnancy or to a woman who is breast-feeding. (See WARNINGS, Pregnancy and Fetal Injury.) Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of TENORETIC 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 other drug therapy. ADVERSE REACTIONS TENORETIC is usually well tolerated in properly selected patients. Most adverse effects have been mild and transient. The adverse effects observed for TENORETIC are essentially the same as those seen with the individual components. Atenolol The frequency estimates in the following table were derived from controlled studies in which adverse reactions were either volunteered by the patient (US studies) or elicited, eg, by checklist (foreign studies). The reported frequency of elicited adverse effects was higher for both atenolol and placebo- treated patients than when these reactions were volunteered. Where frequency of adverse effects for atenolol and placebo is similar, causal relationship to atenolol is uncertain. 14 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ____________________________________________________________________________ Volunteered Total-Volunteered and Elicited (US Studies) (Foreign + US Studies) Atenolol Placebo Atenolol Placebo (n = 164) (n = 206) (n = 399) (n = 407) % % % % CARDIOVASCULAR Bradycardia 3 0 3 0 Cold Extremities 0 0.5 12 5 Postural Hypotension 2 1 4 5 Leg Pain 0 0.5 3 1 CENTRAL NERVOUS SYSTEM/ NEUROMUSCULAR Dizziness 4 1 13 6 Vertigo 2 0.5 2 0.2 Light-Headedness 1 0 3 0.7 Tiredness 0.6 0.5 26 13 Fatigue 3 1 6 5 Lethargy 1 0 3 0.7 Drowsiness 0.6 0 2 0.5 Depression 0.6 0.5 12 9 Dreaming 0 0 3 1 GASTROINTESTINAL Diarrhea 2 0 3 2 Nausea 4 1 3 1 RESPIRATORY (see Warnings) Wheeziness 0 0 3 3 Dyspnea 0.6 1 6 4 During postmarketing experience, the following have been reported in temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin, hallucinations, headache, impotence, Peyronie's disease, postural hypotension which may be associated with syncope, psoriasiform rash or exacerbation of psoriasis, psychoses, purpura, reversible alopecia, thrombocytopenia, visual disturbance, sick sinus syndrome, and dry mouth. TENORETIC, like other beta blockers, has been associated with the development of antinuclear antibodies (ANA), lupus syndrome, and Raynaud’s phenomenon. 15 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chlorthalidone Cardiovascular: orthostatic hypotension; Gastrointestinal: anorexia, gastric irritation, vomiting, cramping, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis; CNS: vertigo, paresthesia, xanthopsia; Hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia; Hypersensitivity: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell's syndrome (toxic epidermal necrolysis); Miscellaneous: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness. Clinical trials of TENORETIC conducted in the United States (89 patients treated with TENORETIC) revealed no new or unexpected adverse effects. POTENTIAL ADVERSE EFFECTS In addition, a variety of adverse effects not observed in clinical trials with atenolol but reported with other beta-adrenergic blocking agents should be considered potential adverse effects of atenolol. Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, decreased performance on neuropsychometrics; Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS); Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis; Hematologic: Agranulocytosis; Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm and respiratory distress. Miscellaneous There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs. The reported incidence is small, and, in most cases, the symptoms have cleared when treatment was withdrawn. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. Patients should be closely monitored following cessation of therapy. (See DOSAGE AND ADMINISTRATION.) 16 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with atenolol (TENORMIN). Furthermore, a number of patients who had previously demonstrated established practolol reactions were transferred to atenolol (TENORMIN) therapy with subsequent resolution or quiescence of the reaction. Clinical Laboratory Test Findings Clinically important changes in standard laboratory parameters were rarely associated with the administration of TENORETIC. The changes in laboratory parameters were not progressive and usually were not associated with clinical manifestations. The most common changes were increases in uric acid and decreases in serum potassium. OVERDOSAGE No specific information is available with regard to overdosage and TENORETIC in humans. Treatment should be symptomatic and supportive and directed to the removal of any unabsorbed drug by induced emesis, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Further consideration should be given to dehydration, electrolyte imbalance and hypotension by established procedures. Atenolol Overdosage with atenolol has been reported with patients surviving acute doses as high as 5 g. One death was reported in a man who may have taken as much as 10 g acutely. The predominant symptoms reported following atenolol overdose are lethargy, disorder of respiratory drive, wheezing, sinus pause, and bradycardia. Additionally, common effects associated with overdosage of any beta-adrenergic blocking agent are congestive heart failure, hypotension, bronchospasm, and/or hypoglycemia. Other treatment modalities should be employed at the physician's discretion and may include: 17 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BRADYCARDIA: Atropine 1-2 mg intravenously. If there is no response to vagal blockade, give isoproterenol cautiously. In refractory cases, a transvenous cardiac pacemaker may be indicated. Glucagon in a 10 mg intravenous bolus has been reported to be useful. If required, this may be repeated or followed by an intravenous infusion of glucagon 1-10 mg/h depending on response. HEART BLOCK (SECOND OR THIRD DEGREE): Isoproterenol or transvenous pacemaker. CONGESTIVE HEART FAILURE: Digitalize the patient and administer a diuretic. Glucagon has been reported to be useful. HYPOTENSION: Vasopressors such as dopamine or norepinephrine (levarterenol). Monitor blood pressure continuously. BRONCHOSPASM: A beta2-stimulant such as isoproterenol or terbutaline and/or aminophylline. HYPOGLYCEMIA: Intravenous glucose. ELECTROLYTE DISTURBANCE: Monitor electrolyte levels and renal function. Institute measures to maintain hydration and electrolytes. Based on the severity of symptoms, management may require intensive support care and facilities for applying cardiac and respiratory support. Chlorthalidone Symptoms of chlorthalidone overdose include nausea, weakness, dizziness and disturbances of electrolyte balance. DOSAGE AND ADMINISTRATION DOSAGE MUST BE INDIVIDUALIZED. (See INDICATIONS AND USAGE.) Chlorthalidone is usually given at a dose of 25 mg daily; the usual initial dose of atenolol is 50 mg daily. Therefore, the initial dose should be one TENORETIC 50 tablet given once a day. If an optimal response is not achieved, the dosage should be increased to one TENORETIC 100 tablet given once a day. Reference ID: 3001215 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda When necessary, another antihypertensive agent may be added gradually beginning with 50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure. Since atenolol is excreted via the kidneys, dosage should be adjusted in cases of severe impairment of renal function. No significant accumulation of atenolol occurs until creatinine clearance falls below 35 mL/min/1.73m2 (normal range is 100-150 mL/min/1.73m2); therefore, the following maximum dosages are recommended for patients with renal impairment. Creatinine Clearance Atenolol Elimination (mL/min/1.73m2) Half-life (hrs) Maximum Dosage 15-35 16-27 50 mg daily <15 >27 50 mg every other day HOW SUPPLIED TENORETIC 50 Tablets (atenolol 50 mg and chlorthalidone 25 mg), NDC 0310-0115, (white, round, biconvex, uncoated tablets with TENORETIC on one side and 115 on the other side, bisected) are supplied in bottles of 100 tablets. TENORETIC 100 Tablets (atenolol 100 mg and chlorthalidone 25 mg), NDC 0310-0117, (white, round, biconvex, uncoated tablets with TENORETIC on one side and 117 on the other side) are supplied in bottles of 100 tablets. Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in well-closed, light-resistant containers. TENORETIC is a trademark of the AstraZeneca group of companies. ©AstraZeneca 2002, 2003, 2004, 2008 Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 By: IPR Pharmaceuticals, Inc. Conóvanas, PR 00729 19 Reference ID: 3001215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda AstraZeneca July 2011 Reference ID: 3001215 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:56.662107	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018760s028lbl.pdf', 'application_number': 18760, 'submission_type': 'SUPPL ', 'submission_number': 28}
11,319	Topicort Ointme ® nt (desoximetasone) 0.25% IC USE ONLY. OR USE IN EYES. Topicort (desoximetasone) Ointment 0.25% contains the active synthetic corticosteroid imarily synthetic t contains 2.5 mg of Desoximetasone in a base esquioleate, , Fatty Acid Pentaerythritol Ester, Aluminum Stearate, Citric Acid, and Butylated Hydroxyanisole. hemical name of desoximetasone is Pregna-1, 4-diene-3, 20-dione, 9-fluoro-11, Desoximetasone has the empirical formula C22H29FO4 and a molecular weight of 376.47. The CAS Registry Number is 382-67-2. The chemical structure is: Topical corticosteroids share anti-inflammatory, anti-pruritic, and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man. FOR DERMATOLOG NOT F Rx Only DESCRIPTION ® desoximetasone. The topical corticosteroids constitute a class of pr steroids used as anti-inflammatory and anti-pruritic agents. Each gram of TOPICORT Ointmen consisting of White Petrolatum USP, Propylene Glycol USP, Sorbitan S Beeswax, Fatty Alcohol Citrate The c 21-dihydroxy-16-methyl-, (11β, 16α)-. CLINICAL PHARMACOLOGY This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics The extent of percutaneous absorption of topical corticosteroids is factors, includin determined by many g the vehicle, the integrity of the epidermal barrier, and the use of ation and/or tion. Occlusive ntially increase the percutaneous absorption of topical corticosteroids. ct for treatment of hrough d corticosteroids. osteroids are Some of the bile. tment 0.25% with y: 0.003 µg/mL) in e blood when it applied topically on the back followed by occlusion for 24 hours. The extent of absorption for the ointment was 7% based on radioactivity recovered from urine and r application, no further radioactivity was detected in urine or n that predominant n to form the glucuronide and sulfate TOPICORT Ointment is indicated for the relief of the inflammatory and pruritic Topical corticosteroids are contraindicated in those patients with a history of ity to any of the components of the preparation. .25% is not for ophthalmic use. PRECAUTIONS General occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflamm other disease processes in the skin increase percutaneous absorp dressings substa Thus, occlusive dressings may be a valuable therapeutic adjun resistant dermatoses. Once absorbed through the skin, topical corticosteroids are handled t pharmacokinetic pathways similar to systemically administere Corticosteroids are bound to plasma proteins in varying degrees. Cortic metabolized primarily in the liver and are then excreted by the kidneys. topical corticosteroids and their metabolites are also excreted into the Pharmacokinetic studies in men with Topicort® (desoximetasone) Oin tagged desoximetasone showed no detectable level (limit of sensitivit 1 subject and 0.004 and 0.006 µg/mL in the remaining 2 subjects in th was feces. Seven days afte feces. Studies with other similarly structured steroids have show metabolite reaction occurs through conjugatio ester. INDICATIONS AND USAGE manifestations of corticosteroid-responsive dermatoses. CONTRAINDICATIONS hypersensitiv WARNINGS Topicort® (desoximetasone) Ointment 0 Keep out of reach of children. Systemic absorption of topical corticosteroids has produced reversible hypothalamic- pituitary-adrenal (HPA) axis suppresion, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Therefore, patients receiving a large dose of a potent topical stero surface area or under an occlusive dressing should be evaluated evidence of HPA axis suppression by using the urinary free cortisol and stimu id applied to a large periodically for ACTH lation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent ally prompt and complete upon discontinuation ay occur, Pediatric patients may absorb proportionally larger amounts of topical corticosteroids NS - Pediatric d and appropriate atological infections, the use of an appropriate antifungal or es not occur the corticosteroid should be discontinued until the infection has been steroid. Recovery of HPA axis function is gener of the drug. Infrequently, signs and symptoms of steroid withdrawal m requiring supplemental systemic corticosteroids. and thus be more susceptible to systemic toxicity (See PRECAUTIO Use). If irritation develops, topical corticosteroids should be discontinue therapy instituted. In the presence of derm antibacterial agent should be instituted. If a favorable response do promptly, adequately controlled. Information for the Patient Patients using topical corticosteroids should receive the following inform nstructions: ation and i s for external use ntact with the eyes. rder other than for 3. The treated skin area should not be bandaged or otherwise covered or wrapped as sive unless directed by the physician. cially under . patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may 1. This medication is to be used as directed by the physician. It i only. Avoid co 2. Patients should be advised not to use this medication for any diso which it was prescribed. to be occlu 4. Patients should report any signs of local adverse reactions, espe occlusive dressing 5. Parents of pediatric constitute occlusive dressings. Laboratory Tests The following tests may be helpful in evaluating the hypothalamic-pituitary-adrenal (HPA) axis suppression: Urinary free cortisol test ACTH stimulation test Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of desoximetasone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Desoximetasone was nonmutagenic in the Ames test. ry C Pregnancy Category: Teratogenic Effects: Pregnancy Catego ls when administered systemically at relatively low dosage levels. Some corticosteroids have als. bryotoxic in mice, rats, and in doses 3 to 30 . n teratogenic steroids. Therefore, TOPICORT Ointment should g pregnancy only if the potential benefit justifies the potential risk to the tients, in large Corticosteroids have been shown to be teratogenic in laboratory anima been shown to be teratogenic after dermal application in laboratory anim Desoximetasone has been shown to be teratogenic and em rabbits when given by subcutaneous or dermal routes of administration times the human dose of Topicort® (desoximetasone) Ointment 0.25% There are no adequate and well-controlled studies in pregnant women o effects from topically applied cortico be used durin fetus. Drugs of this class should not be used extensively on pregnant pa amounts, or for prolonged periods of time. Nursing Mothers It is not known whether topical administration of corticosteroids could result in sufficient bsorption to produce detectable quantities in breast milk. Systemically quantities not likely to have xercised when systemic a administered corticosteroids are secreted into breast milk in a deleterious effect on the infant. Nevertheless, caution should be e topical corticosteroids are administered to a nursing woman. Pediatric Use Pediatric patients may demonstrate greater susceptibility to t corticosteroid-induced HPA axis suppression and Cushing’s syndro mature patients because of a larger skin surface area to bod HPA axis suppression, Cushing’s syndro opical me than y weight ratio. me, and intracranial hypertension have been Manifestations of adrenal suppression in pediatric patients include linear growth sence of response to ude bulging a. hould be limited to the and development of pediatric patients. Safety and effectiveness of TOPICORT Ointment in pediatric patients below the age of 10 have not been established. ADVERSE REACTIONS The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, reported in pediatric patients receiving topical corticosteroids. retardation, delayed weight gain, low plasma cortisol levels, and ab ACTH stimulation. Manifestations of intracranial hypertension incl fontanelles, headaches, and bilateral papilledem Administration of topical corticosteroids to pediatric patients s least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae and miliaria. as low (0.3%) for Topicort (desoximetasone) Ointment 0.25% and consisted of development of at the site of application. ids can be absorbed in sufficient amount to produce DOSAGE AND ADMINISTRATION lm of TOPICORT Ointment to the affected skin areas twice daily. Rub in Topicort (desoximetasone) Ointment 0.25% is supplied in 15 gram m (NDC 99207-025-60) tubes. ature 15° - 30°C (59° - 86°F). for: atology Company® Phoenix, AZ 85018 by: Hoechst Marion Roussel Deutschland GmbH, D-65926 Frankfurt am Main Made in Germany REG TM HOECHST AG In controlled clinical studies the incidence of adverse reactions w ® comedones OVERDOSAGE Topically applied corticostero systemic effects (See PRECAUTIONS). Apply a thin fi gently. HOW SUPPLIED ® (NDC 99207-025-15), and 60 gra Store at controlled room temper Prescribing Information as of April 1999. Manufactured MEDICIS, The Derm This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:56.716276	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18763slr003_topicort_lbl.pdf', 'application_number': 18763, 'submission_type': 'SUPPL ', 'submission_number': 3}
11,318	s t ructural formula s tructural formula TENORETIC® (atenolol and chlorthalidone) DESCRIPTION TENORETIC® (atenolol and chlorthalidone) is for the treatment of hypertension. It combines the antihypertensive activity of two agents: a beta1-selective (cardioselective) hydrophilic blocking agent (atenolol, TENORMIN®) and a monosulfonamyl diuretic (chlorthalidone). Atenolol is Benzeneacetamide, 4-[2'-hydroxy-3'-[(1-methylethyl) amino] propoxy]-. Atenolol (free base) is a relatively polar hydrophilic compound with a water solubility of 26.5 mg/mL at 37° C. It is freely soluble in 1N HCl (300 mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at 25°C). Chlorthalidone is 2-Chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl) benzene sulfonamide: Chlorthalidone has a water solubility of 12 mg/100 mL at 20°C. Each TENORETIC 100 Tablet contains: Atenolol (TENORMIN®).......................................100 mg Chlorthalidone........................................................ 25 mg Each TENORETIC 50 Tablet contains: Atenolol (TENORMIN®).........................................50 mg Chlorthalidone..........................................................25 mg Inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Reference ID: 3210459 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Tenoretic Atenolol and chlorthalidone have been used singly and concomitantly for the treatment of hypertension. The antihypertensive effects of these agents are additive, and studies have shown that there is no interference with bioavailability when these agents are given together in the single combination tablet. Therefore, this combination provides a convenient formulation for the concomitant administration of these two entities. In patients with more severe hypertension, TENORETIC may be administered with other antihypertensives such as vasodilators. Atenolol: Atenolol is a beta1-selective (cardioselective) beta-adrenergic receptor blocking agent without membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities. This preferential effect is not absolute, however, and at higher doses, atenolol inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Pharmacodynamics In standard animal or human pharmacological tests, beta-adrenoreceptor blocking activity of atenolol has been demonstrated by: (1) reduction in resting and exercise heart rates and cardiac output, (2) reduction of systolic and diastolic blood pressure at rest and on exercise, (3) inhibition of isoproterenol induced tachycardia and (4) reduction in reflex orthostatic tachycardia. A significant beta-blocking effect of atenolol, as measured by reduction of exercise tachycardia, is apparent within one hour following oral administration of a single dose. This effect is maximal at about 2 to 4 hours and persists for at least 24 hours. The effect at 24 hours is dose related and also bears a linear relationship to the logarithm of plasma atenolol concentration. However, as has been shown for all beta blocking agents, the antihypertensive effect does not appear to be related to plasma level. In normal subjects, the beta1-selectivity of atenolol has been shown by its reduced ability to reverse the beta2-mediated vasodilating effect of isoproterenol as compared to equivalent beta-blocking doses of propranolol. In asthmatic patients, a dose of atenolol producing a greater effect on resting heart rate than propranolol resulted in much less increase in airway resistance. In a placebo controlled comparison of approximately equipotent oral doses of several beta blockers, atenolol produced a significantly smaller decrease of FEV1 than nonselective beta blockers, such as propranolol and unlike those agents did not inhibit bronchodilation in response to isoproterenol. Consistent with its negative chronotropic effect due to beta blockade of the SA node, atenolol increases sinus cycle length and sinus node recovery time. Conduction in the AV node is also prolonged. Atenolol is devoid of membrane stabilizing activity, and increasing the dose well beyond that producing beta blockade does not further depress myocardial contractility. Several studies have demonstrated a moderate (approximately 10%) increase in stroke volume at rest and exercise. 2 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In controlled clinical trials, atenolol given as a single daily dose, was an effective antihypertensive agent providing 24-hour reduction of blood pressure. Atenolol has been studied in combination with thiazide-type diuretics and the blood pressure effects of the combination are approximately additive. Atenolol is also compatible with methyldopa, hydralazine and prazosin, the combination resulting in a larger fall in blood pressure than with the single agents. The dose range of atenolol is narrow, and increasing the dose beyond 100 mg once daily is not associated with increased antihypertensive effect. The mechanisms of the antihypertensive effects of beta-blocking agents have not been established. Several mechanisms have been proposed and include: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output, (2) a central effect leading to reduced sympathetic outflow to the periphery and (3) suppression of renin activity. The results from long-term studies have not shown any diminution of the antihypertensive efficacy of atenolol with prolonged use. Pharmacokinetics and Metabolism In man, absorption of an oral dose is rapid and consistent but incomplete. Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, the remainder being excreted unchanged in the feces. Peak blood levels are reached between 2 and 4 hours after ingestion. Unlike propranolol or metoprolol, but like nadolol, hydrophilic atenolol undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion. Atenolol also differs from propranolol in that only a small amount (6 - 16%) is bound to proteins in the plasma. This kinetic profile results in relatively consistent plasma drug levels with about a fourfold interpatient variation. There is no information as to the pharmacokinetic effect of atenolol on chlorthalidone. The elimination half-life of atenolol is approximately 6 to 7 hours and there is no alteration of the kinetic profile of the drug by chronic administration. Following doses of 50 mg or 100 mg, both beta-blocking and antihypertensive effects persist for at least 24 hours. When renal function is impaired, elimination of atenolol is closely related to the glomerular filtration rate; but significant accumulation does not occur until the creatinine clearance falls below 35 mL/min/1.73m2 (see prescribing information for atenolol [TENORMIN®]). Atenolol Geriatric Pharmacology In general, elderly patients present higher atenolol plasma levels with total clearance values about 50% lower than younger subjects. The half-life is markedly longer in the elderly compared to younger subjects. The reduction of atenolol clearance follows the general trend that the elimination of renally excreted drugs is decreased with increasing age. 3 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chlorthalidone: Chlorthalidone is a monosulfonamyl diuretic which differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is an oral diuretic with prolonged action and low toxicity. The diuretic effect of the drug occurs within 2 hours of an oral dose. It produces diuresis with greatly increased excretion of sodium and chloride. At maximal therapeutic dosage, chlorthalidone is approximately equal in its diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics. The site of action appears to be the cortical diluting segment of the ascending limb of Henle's loop of the nephron. INDICATIONS AND USAGE TENORETIC is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including atenolol and chlorthalidone. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (eg, on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. 4 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This fixed dose combination drug is not indicated for initial therapy of hypertension. If the fixed dose combination represents the dose appropriate to the individual patient's needs, it may be more convenient than the separate components. CONTRAINDICATIONS TENORETIC is contraindicated in patients with: sinus bradycardia; heart block greater than first degree; cardiogenic shock; overt cardiac failure (see WARNINGS); anuria; hypersensitivity to this product or to sulfonamide-derived drugs. WARNINGS Cardiac Failure Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. IN PATIENTS WITHOUT A HISTORY OF CARDIAC FAILURE, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately according to currently recommended guidelines, and the response observed closely. If cardiac failure continues despite adequate treatment, TENORETIC should be withdrawn. (See DOSAGE AND ADMINISTRATION.) Renal and Hepatic Disease and Electrolyte Disturbances Since atenolol is excreted via the kidneys, TENORETIC should be used with caution in patients with impaired renal function. In patients with renal disease, thiazides may precipitate azotemia. Since cumulative effects may develop in the presence of impaired renal function, if progressive renal impairment becomes evident, TENORETIC should be discontinued. In patients with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. TENORETIC should be used with caution in these patients. Ischemic Heart Disease Following abrupt cessation of therapy with certain beta-blocking agents in patients with coronary artery disease, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported. Therefore, such patients should be cautioned against interruption of therapy without the physician's advice. Even in the absence of overt angina pectoris, when discontinuation of TENORETIC is planned, the patient should be carefully observed and should be advised to limit physical activity to a minimum. TENORETIC should be reinstated if withdrawal symptoms occur. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue TENORETIC therapy abruptly even in patients treated only for hypertension. Reference ID: 3210459 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concomitant Use of Calcium Channel Blockers Bradycardia and heart block can occur and the left ventricular end diastolic pressure can rise when beta-blockers are administered with verapamil or diltiazem. Patients with pre-existing conduction abnormalities or left ventricular dysfunction are particularly susceptible. (See PRECAUTIONS.) Bronchospastic Diseases PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta1-selectivity, however, TENORETIC may be used with caution in patients with bronchospastic disease who do not respond to or cannot tolerate, other antihypertensive treatment. Since beta1-selectivity is not absolute, the lowest possible dose of TENORETIC should be used and a beta2-stimulating agent (bronchodilator) should be made available. If dosage must be increased, dividing the dose should be considered in order to achieve lower peak blood levels. 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. Metabolic and Endocrine Effects TENORETIC may be used with caution in diabetic patients. Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. At recommended doses atenolol does not potentiate insulin-induced hypoglycemia and, unlike nonselective beta blockers, does not delay recovery of blood glucose to normal levels. Insulin requirements in diabetic patients may be increased, decreased or unchanged; latent diabetes mellitus may become manifest during chlorthalidone administration. Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom TENORETIC therapy is to be withdrawn should be monitored closely. Because calcium excretion is decreased by thiazides, TENORETIC should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy; however, the common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen. Hyperuricemia may occur, or acute gout may be precipitated in certain patients receiving thiazide therapy. 6 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Untreated Pheochromocytoma TENORETIC should not be given to patients with untreated pheochromocytoma. Pregnancy and Fetal Injury Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the placental barrier and appears in cord blood. Administration of atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age. No studies have been performed on the use of atenolol in the first trimester and the possibility of fetal injury cannot be excluded. 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. Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORETIC is administered during pregnancy or to a woman who is breast-feeding. (See PRECAUTIONS, Nursing Mothers.) TENORETIC was studied for teratogenic potential in the rat and rabbit. Doses of atenolol/chlorthalidone of 8/2, 80/20, and 240/60 mg/kg/day were administered orally to pregnant rats with no evidence of embryofetotoxicity observed. Two studies were conducted in rabbits. In the first study, pregnant rabbits were dosed with 8/2, 80/20, and 160/40 mg/kg/day of atenolol/chlorthalidone. No teratogenic effects were noted, but embryonic resorptions were observed at all dose levels (ranging from approximately 5 times to 100 times the maximum recommended human dose). In the second rabbit study, doses of atenolol/chlorthalidone were 4/1, 8/2, and 20/5 mg/kg/day. No teratogenic or embryotoxic effects were demonstrated. Atenolol Atenolol has been shown to produce a dose-related increase in embryo/fetal resorptions in rats at doses equal to or greater than 50 mg/kg/day or 25 or more times the maximum recommended human antihypertensive dose. Although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg/day or 12.5 times the maximum recommended human antihypertensive dose.* Chlorthalidone Thiazides cross the placental barrier and appear in cord blood. The use of chlorthalidone and related drugs in pregnant women requires that the anticipated benefits of the drug be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult. Based on the maximum dose of 100 mg/day in a 50 kg patient. PRECAUTIONS General TENORETIC may aggravate peripheral arterial circulatory disorders. 7 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Electrolyte and Fluid Balance Status Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Patients should be observed for clinical signs of fluid or electrolyte imbalance; i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Measurement of potassium levels is appropriate especially in elderly patients, those receiving digitalis preparations for cardiac failure, patients whose dietary intake of potassium is abnormally low, or those suffering from gastrointestinal complaints. Hypokalemia may develop especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids or ACTH. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (eg, increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high potassium content. Any chloride deficit during thiazide therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Drug Interactions TENORETIC may potentiate the action of other antihypertensive agents used concomitantly. Patients treated with TENORETIC plus a catecholamine depletor (eg, reserpine) should be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope or postural hypotension. Calcium channel blockers may also have an additive effect when given with TENORETIC. (See WARNINGS.) Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects. Disopyramide has been associated with severe bradycardia, asystole and heart failure when administered with beta blockers. 8 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta blockers. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude the therapeutic effectiveness of norepinephrine. Thiazides may increase the responsiveness to tubocurarine. Concomitant use of prostaglandin synthase inhibiting drugs, eg, indomethacin, may decrease the hypotensive effects of beta blockers. Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such preparations with TENORETIC. Beta blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta blocker should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta blockers should be delayed for several days after clonidine administration has stopped. While taking beta blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Other Precautions In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. The possible exacerbation or activation of systemic lupus erythematosus has been reported. The antihypertensive effects of thiazides may be enhanced in the postsympathectomy patient. Carcinogenesis, Mutagenesis, Impairment of Fertility Two long-term (maximum dosing duration of 18 or 24 months) rat studies and one long-term (maximum dosing duration of 18 months) mouse study, each employing dose levels as high as 300 mg/kg/day or 150 times the maximum recommended human antihypertensive dose, did not indicate a carcinogenic potential of atenolol. A third (24 month) rat study, employing doses of 500 and 1,500 mg/kg/day (250 and 750 times the maximum recommended human antihypertensive dose) resulted in increased incidences of benign adrenal medullary tumors in males and females, mammary fibroadenomas in females, and anterior pituitary adenomas and thyroid parafollicular cell carcinomas in males. No evidence of a mutagenic potential of atenolol was uncovered in the dominant lethal test (mouse), in vivo cytogenetics test (Chinese hamster) or Ames test (S typhimurium). Reference ID: 3210459 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Based on the maximum dose of 100 mg/day in a 50 kg patient. Fertility of male or female rats (evaluated at dose levels as high as 200 mg/kg/day or 100 times the maximum recommended human dose) was unaffected by atenolol administration. Animal Toxicology Six month oral administration studies were conducted in rats and dogs using TENORETIC doses up to 12.5 mg/kg/day (atenolol/chlorthalidone 10/2.5 mg/kg/day -- approximately five times the maximum recommended human antihypertensive dose). There were no functional or morphological abnormalities resulting from dosing either compound alone or together other than minor changes in heart rate, blood pressure and urine chemistry which were attributed to the known pharmacologic properties of atenolol and/or chlorthalidone. Chronic studies of atenolol performed in animals have revealed the occurrence of vacuolation of epithelial cells of Brunner's glands in the duodenum of both male and female dogs at all tested dose levels (starting at 15 mg/kg/day or 7.5 times the maximum recommended human antihypertensive dose) and increased incidence of atrial degeneration of hearts of male rats at 300 but not 150 mg atenolol/kg/day (150 and 75 times the maximum recommended human antihypertensive dose, respectively). Use in Pregnancy Pregnancy Category D: See WARNINGS - Pregnancy and Fetal Injury. Nursing Mothers Atenolol is excreted in human breast milk at a ratio of 1.5 to 6.8 when compared to the concentration in plasma. Caution should be exercised when atenolol is administered to a nursing woman. Clinically significant bradycardia has been reported *Based on the maximum dose of 100 mg/day in a 50 kg patient. in breast-fed infants. Premature infants, or infants with impaired renal function, may be more likely to develop adverse effects. Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORETIC is administered during pregnancy or to a woman who is breast-feeding. (See WARNINGS, Pregnancy and Fetal Injury.) Pediatric Use Safety and effectiveness in pediatric patients have not been established. 10 Reference ID: 3210459 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 TENORETIC 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 other drug therapy. ADVERSE REACTIONS TENORETIC is usually well tolerated in properly selected patients. Most adverse effects have been mild and transient. The adverse effects observed for TENORETIC are essentially the same as those seen with the individual components. Atenolol The frequency estimates in the following table were derived from controlled studies in which adverse reactions were either volunteered by the patient (US studies) or elicited, eg, by checklist (foreign studies). The reported frequency of elicited adverse effects was higher for both atenolol and placebo-treated patients than when these reactions were volunteered. Where frequency of adverse effects for atenolol and placebo is similar, causal relationship to atenolol is uncertain. 11 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ____________________________________________________________________________ Volunteered Total-Volunteered and Elicited (US Studies) (Foreign + US Studies) Atenolol Placebo Atenolol Placebo (n = 164) (n = 206) (n = 399) (n = 407) % % % % CARDIOVASCULAR Bradycardia 3 0 3 0 Cold Extremities 0 0.5 12 5 Postural Hypotension 2 1 4 5 Leg Pain 0 0.5 3 1 CENTRAL NERVOUS SYSTEM/ NEUROMUSCULAR Dizziness 4 1 13 6 Vertigo 2 0.5 2 0.2 Light-Headedness 1 0 3 0.7 Tiredness 0.6 0.5 26 13 Fatigue 3 1 6 5 Lethargy 1 0 3 0.7 Drowsiness 0.6 0 2 0.5 Depression 0.6 0.5 12 9 Dreaming 0 0 3 1 GASTROINTESTINAL Diarrhea 2 0 3 2 Nausea 4 1 3 1 RESPIRATORY (see Warnings) Wheeziness 0 0 3 3 Dyspnea 0.6 1 6 4 During postmarketing experience, the following have been reported in temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin, hallucinations, headache, impotence, Peyronie's disease, postural hypotension which may be associated with syncope, psoriasiform rash or exacerbation of psoriasis, psychoses, purpura, reversible alopecia, thrombocytopenia, visual disturbance, sick sinus syndrome, and dry mouth. TENORETIC, like other beta blockers, has been associated with the development of antinuclear antibodies (ANA), lupus syndrome, and Raynaud’s phenomenon. 12 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chlorthalidone Cardiovascular: orthostatic hypotension; Gastrointestinal: anorexia, gastric irritation, vomiting, cramping, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis; CNS: vertigo, paresthesia, xanthopsia; Hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia; Hypersensitivity: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell's syndrome (toxic epidermal necrolysis); Miscellaneous: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness. Clinical trials of TENORETIC conducted in the United States (89 patients treated with TENORETIC) revealed no new or unexpected adverse effects. POTENTIAL ADVERSE EFFECTS In addition, a variety of adverse effects not observed in clinical trials with atenolol but reported with other beta-adrenergic blocking agents should be considered potential adverse effects of atenolol. Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, decreased performance on neuropsychometrics; Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS); Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis; Hematologic: Agranulocytosis; Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm and respiratory distress. Miscellaneous There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs. The reported incidence is small, and, in most cases, the symptoms have cleared when treatment was withdrawn. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. Patients should be closely monitored following cessation of therapy. (See DOSAGE AND ADMINISTRATION.) The oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with atenolol (TENORMIN). Furthermore, a number of patients who had previously demonstrated established practolol reactions were transferred to atenolol (TENORMIN) therapy with subsequent resolution or quiescence of the reaction. Clinical Laboratory Test Findings Clinically important changes in standard laboratory parameters were rarely associated with the administration of TENORETIC. The changes in laboratory parameters were not progressive and usually were not associated with clinical manifestations. The most common changes were increases in uric acid and decreases in serum potassium. 13 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE No specific information is available with regard to overdosage and TENORETIC in humans. Treatment should be symptomatic and supportive and directed to the removal of any unabsorbed drug by induced emesis, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Further consideration should be given to dehydration, electrolyte imbalance and hypotension by established procedures. Atenolol Overdosage with atenolol has been reported with patients surviving acute doses as high as 5 g. One death was reported in a man who may have taken as much as 10 g acutely. The predominant symptoms reported following atenolol overdose are lethargy, disorder of respiratory drive, wheezing, sinus pause, and bradycardia. Additionally, common effects associated with overdosage of any beta-adrenergic blocking agent are congestive heart failure, hypotension, bronchospasm, and/or hypoglycemia. Other treatment modalities should be employed at the physician's discretion and may include: BRADYCARDIA: Atropine 1-2 mg intravenously. If there is no response to vagal blockade, give isoproterenol cautiously. In refractory cases, a transvenous cardiac pacemaker may be indicated. Glucagon in a 10 mg intravenous bolus has been reported to be useful. If required, this may be repeated or followed by an intravenous infusion of glucagon 1-10 mg/h depending on response. HEART BLOCK (SECOND OR THIRD DEGREE): Isoproterenol or transvenous pacemaker. CONGESTIVE HEART FAILURE: Digitalize the patient and administer a diuretic. Glucagon has been reported to be useful. HYPOTENSION: Vasopressors such as dopamine or norepinephrine (levarterenol). Monitor blood pressure continuously. BRONCHOSPASM: A beta2-stimulant such as isoproterenol or terbutaline and/or aminophylline. HYPOGLYCEMIA: Intravenous glucose. ELECTROLYTE DISTURBANCE: Monitor electrolyte levels and renal function. Institute measures to maintain hydration and electrolytes. Based on the severity of symptoms, management may require intensive support care and facilities for applying cardiac and respiratory support. Chlorthalidone Symptoms of chlorthalidone overdose include nausea, weakness, dizziness and disturbances of electrolyte balance. Reference ID: 3210459 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15-35 16-27 50 mg daily <15 >27 50 mg every other day HOW SUPPLIED DOSAGE AND ADMINISTRATION DOSAGE MUST BE INDIVIDUALIZED. (See INDICATIONS AND USAGE.) Chlorthalidone is usually given at a dose of 25 mg daily; the usual initial dose of atenolol is 50 mg daily. Therefore, the initial dose should be one TENORETIC 50 tablet given once a day. If an optimal response is not achieved, the dosage should be increased to one TENORETIC 100 tablet given once a day. When necessary, another antihypertensive agent may be added gradually beginning with 50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure. Since atenolol is excreted via the kidneys, dosage should be adjusted in cases of severe impairment of renal function. No significant accumulation of atenolol occurs until creatinine clearance falls below 35 mL/min/1.73m2 (normal range is 100-150 mL/min/1.73m2); therefore, the following maximum dosages are recommended for patients with renal impairment. Creatinine Clearance Atenolol Elimination (mL/min/1.73m2) Half-life (hrs) Maximum Dosage TENORETIC 50 Tablets (atenolol 50 mg and chlorthalidone 25 mg), NDC 0310-0115, (white, round, biconvex, uncoated tablets with TENORETIC on one side and 115 on the other side, bisected) are supplied in bottles of 100 tablets. TENORETIC 100 Tablets (atenolol 100 mg and chlorthalidone 25 mg), NDC 0310-0117, (white, round, biconvex, uncoated tablets with TENORETIC on one side and 117 on the other side) are supplied in bottles of 100 tablets. Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in well-closed, light-resistant containers. TENORETIC is a trademark of the AstraZeneca group of companies. ©AstraZeneca 2012 Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 By: IPR Pharmaceuticals, Inc. Canóvanas, PR 00729 15 Reference ID: 3210459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Revised: 10/2012 AstraZeneca Reference ID: 3210459 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:56.824577	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018760s029lbl.pdf', 'application_number': 18760, 'submission_type': 'SUPPL ', 'submission_number': 29}
11,320	NDA 18-766/S-013 Page 3 Ansaid flurbiprofen tablets, USP Ansaid (flurbiprofen tablets, USP) 50mg and 10 mg Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS). • ANSAID® is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (See WARNINGS). DESCRIPTION ANSAID Tablets contain flurbiprofen, which is a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drugs. ANSAID Tablets are white, oval, film-coated tablets for oral administration. Flurbiprofen is a racemic mixture of (+)S- and (-)R- enantiomers. Flurbiprofen is a white or slightly yellow crystalline powder. It is slightly soluble in water at pH 7.0 and readily soluble in most polar solvents. The chemical name is [1,1’-biphenyl]-4-acetic acid, 2-fluoro-alpha- methyl-, (±)-. The molecular weight is 244.26. Its molecular formula is C15H13FO2 and it has the following structural formula: The inactive ingredients in ANSAID (both strengths) include carnauba wax, colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, and titanium dioxide. In addition, the 100 mg tablet contains FD&C Blue No. 2. CLINICAL PHARMACOLOGY Pharmacodynamics ANSAID Tablets contain flurbiprofen, a nonsteroidal anti-inflammatory drug that exhibits anti- inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of ANSAID, like that of other nonsteroidal anti-inflammatory drugs, is not completely understood but This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 4 may be related to prostaglandin synthetase inhibition. Pharmacokinetics Absorption: The mean oral bioavailability of flurbiprofen from ANSAID Tablets 100 mg is 96% rel- ative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed from ANSAID, with peak plasma concentrations occurring at about 2 hours (see Table 1). Administration of ANSAID with either food or antacids may alter the rate but not the extent of flurbiprofen absorption. Ranitidine has been shown to have no effect on either the rate or extent of flurbiprofen absorption from ANSAID. Distribution: The apparent volume of distribution (Vz/F) of both R- and S-flurbiprofen is approxi- mately 0.12 L/Kg. Both flurbiprofen enantiomers are more than 99% bound to plasma proteins, pri- marily albumin. Plasma protein binding is relatively constant for the typical average steady-state concentrations (≤10 µg/mL) achieved with recommended doses. Flurbiprofen is poorly excreted into human milk. The nursing infant dose is predicted to be approximately 0.1 mg/day in the established milk of a woman taking ANSAID 200 mg/day (see PRECAUTIONS, Nursing Mothers). Metabolism: Several flurbiprofen metabolites have been identified in human plasma and urine. These metabolites include 4’-hydroxy-flurbiprofen, 3’, 4’-dihydroxy-flurbiprofen, 3’-hydroxy-4’-methoxy- flurbiprofen, their conjugates, and conjugated flurbiprofen. Unlike other arylpropionic acid derivatives (eg, ibuprofen), metabolism of R-flurbiprofen to S-flurbiprofen is minimal. In vitro studies have demonstrated that cytochrome P450 2C9 plays an important role in the metabolism of flurbiprofen to its major metabolite, 4’-hydroxy-flurbiprofen. The 4’-hydroxy-flurbiprofen metabolite showed little anti-inflammatory activity in animal models of inflammation. Flurbiprofen does not induce enzymes that alter its metabolism. The total plasma clearance of unbound flurbiprofen is not stereoselective, and clearance of flur- biprofen is independent of dose when used within the therapeutic range. Excretion: Following dosing with ANSAID, less than 3% of flurbiprofen is excreted unchanged in the urine, with about 70% of the dose eliminated in the urine as parent drug and metabolites. Because renal elimination is a significant pathway of elimination of flurbiprofen metabolites, dosing adjustment in patients with moderate or severe renal dysfunction may be necessary to avoid accumulation of flurbiprofen metabolites. The mean terminal disposition half-lives (t½) of R- and S-flurbiprofen are similar, about 4.7 and 5.7 hours, respectively. There is little accumulation of flurbiprofen following multiple doses of ANSAID. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 5 Table 1. Mean (SD) R,S-Flurbiprofen Pharmacokinetic Parameters Normalized to a 100 mg Dose of ANSAID Pharmacokinetic Parameter Normal Healthy Adults* (18 to 40 years) N=15 Geriatric Arthritis Patients† (65 to 83 years) N=13 End Stage Renal Disease Patients* (23 to 42 years) N=8 Alcoholic Cirrhosis Patients‡ (31 to 61 years) N=8 Peak Concentration (Tg/mL) 14 (4) 16 (5) 9§ 9§ Time of Peak Concentration (h) 1.9 (1.5) 2.2 (3) 2.3§ 1.2§ Urinary Recovery of Unchanged Flurbiprofen (% of Dose) 2.9 (1.3) 0.6 (0.6) 0.02 (0.02) NA║ Area Under the Curve (AUC)¶ (Tg h/mL) 83 (20) 77 (24) 44§ 50§ Apparent Volume of Distribution (Vz/F, L) 14 (3) 12 (5) 10§ 14§ Terminal Disposition Half-life (t½, h) 7.5 (0.8) 5.8 (1.9) 3.3# 5.4# *100 mg single-dose † Steady-state evaluation of 100 mg every 12 hours ‡ 200 mg single-dose § Calculated from mean parameter values of both flurbiprofen enantiomers ║ Not available ¶ AUC from 0 to infinity for single doses and from 0 to the end of the dosing interval for multiple- doses # Value for S-flurbiprofen Special Populations Pediatric: The pharmacokinetics of flurbiprofen have not been investigated in pediatric patients. Race: No pharmacokinetic differences due to race have been identified. Geriatric: Flurbiprofen pharmacokinetics were similar in geriatric arthritis patients, younger arthritis patients, and young healthy volunteers receiving ANSAID Tablets 100 mg as either single or multiple doses. Hepatic insufficiency: Hepatic metabolism may account for >90% of flurbiprofen elimination, so patients with hepatic disease may require reduced doses of ANSAID Tablets compared to patients with normal hepatic function. The pharmacokinetics of R- and S-flurbiprofen were similar, however, in alcoholic cirrhosis patients (N=8) and young healthy volunteers (N=8) following administration of a single 200 mg dose of ANSAID tablets. Flurbiprofen plasma protein binding may be decreased in patients with liver disease and serum albumin concentrations below 3.1 g/dL (see PRECAUTIONS, Hepatic Effects). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 6 Renal insufficiency: Renal clearance is an important route of elimination for flurbiprofen metabolites, but a minor route of elimination for unchanged flurbiprofen (≤3% of total clearance). The unbound clearances of R- and S-flurbiprofen did not differ significantly between normal healthy volunteers (N=6, 50 mg single dose) and patients with renal impairment (N=8, inulin clearances ranging from 11 to 43 mL/min, 50 mg multiple doses). Flurbiprofen plasma protein binding may be decreased in patients with renal impairment and serum albumin concentrations below 3.9 g/dL. Elimination of flurbiprofen metabolites may be reduced in patients with renal impairment (see PRECAUTIONS, Renal Effects). Flurbiprofen is not significantly removed from the blood into dialysate in patients undergoing contin- uous ambulatory peritoneal dialysis. Drug-Drug Interactions (see also PRECAUTIONS, Drug Interactions) Antacids: Administration of ANSAID to volunteers under fasting conditions or with antacid suspen- sion yielded similar serum flurbiprofen-time profiles in young adult subjects (n=12). In geriatric subjects (n=7), there was a reduction in the rate but not the extent of flurbiprofen absorption. Aspirin: Concurrent administration of ANSAID and aspirin resulted in 50% lower serum flurbiprofen concentrations. This effect of aspirin (which is also seen with other nonsteroidal anti-inflammatory drugs) has been demonstrated in patients with rheumatoid arthritis (n=15) and in healthy volunteers (n=16) (see PRECAUTIONS, Drug Interactions). Beta-adrenergic blocking agents: The effect of flurbiprofen on blood pressure response to propranolol and atenolol was evaluated in men with mild uncomplicated hypertension (n=10). Flurbiprofen pretreatment attenuated the hypotensive effect of a single dose of propranolol but not atenolol. Flurbiprofen did not appear to affect the beta-blocker-mediated reduction in heart rate. Flurbiprofen did not affect the pharmacokinetic profile of either drug (see PRECAUTIONS, Drug Interactions). Cimetidine, Ranitidine: In normal volunteers (n=9), pretreatment with cimetidine or ranitidine did not affect flurbiprofen pharmacokinetics, except for a small (13%) but statistically significant increase in the area under the serum concentration curve of flurbiprofen in subjects who received cimetidine. Digoxin: In studies of healthy males (n=14), concomitant administration of flurbiprofen and digoxin did not change the steady state serum levels of either drug. Diuretics: Studies in healthy volunteers have shown that, like other nonsteroidal anti-inflammatory drugs, flurbiprofen can interfere with the effects of furosemide. Although results have varied from study to study, effects have been shown on furosemide-stimulated diuresis, natriuresis, and kaliuresis. Other nonsteroidal anti-inflammatory drugs that inhibit prostaglandin synthesis have been shown to interfere with thiazide and potassium-sparing diuretics (see PRECAUTIONS, Drug Interactions). Lithium: In a study of 11 women with bipolar disorder receiving lithium carbonate at a dosage of 600 to 1200 mg/day, administration of 100 mg ANSAID every 12 hours increased plasma lithium concentrations by 19%. Four of 11 patients experienced a clinically important increase (>25% or >0.2 mmol/L). Nonsteroidal anti-inflammatory drugs have also been reported to decrease the renal clearance of lithium by about 20% (see PRECAUTIONS, Drug Interactions). Methotrexate: In a study of six adult arthritis patients, coadministration of methotrexate (10 to 25 mg/dose) and ANSAID (300 mg/day) resulted in no observable interaction between these two drugs. Oral Hypoglycemic Agents: In a clinical study, flurbiprofen was administered to adult diabetics who were already receiving glyburide (n=4), metformin (n=2), chlorpropamide with phenformin (n=3), or glyburide with phenformin (n=6). Although there was a slight reduction in blood sugar concentrations during concomitant administration of flurbiprofen and hypoglycemic agents, there were no signs or symptoms of hypoglycemia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 7 INDICATIONS AND USAGE Carefully consider the potential benefits and risks of ANSAID and other treatment options before deciding to use ANSAID. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). ANSAID is indicated: • For relief of the signs and symptoms of rheumatoid arthritis. • For relief of the signs and symptoms of osteoarthritis. CONTRAINDICATIONS ANSAID Tablets are contraindicated in patients with known hypersensitivity to flurbiprofen. ANSAID should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other nonsteroidal anti-inflammatory drugs. Severe, rarely fatal, ana- phylactic-like reactions to nonsteroidal anti-inflammatory drugs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma). ANSAID is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see GI WARNINGS). Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension NSAIDs including ANSAID, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ANSAID, should be used with caution in patients with hypertension. Blood This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 8 pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. ANSAID should be used with caution in patients with fluid retention or heart failure. Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including ANSAID, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti- inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease In clinical studies, the elimination half-life of flurbiprofen was unchanged in patients with renal impairment. Flurbiprofen metabolites are eliminated primarily by the kidneys. Elimination of 4’- hydroxy-flurbiprofen was reduced in patients with moderate to severe renal impairment. Therefore, treatment with ANSAID is not recommended in these patients with advanced renal disease. If ANSAID therapy must be initiated, close monitoring of the patients renal function is advisable (see CLINICAL PHARMACOLOGY). No information is available form controlled clinical studies regarding the use of ANSAID in patients with advanced renal disease. Therefore, treatment with ANSAID is not recommended in these patients This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 9 with advanced renal disease. If ANSAID therapy must be initiated, close monitoring of the patients renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ANSAID. ANSAID should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Pregnancy In late pregnancy, as with other NSAIDs, ANSAID should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General ANSAID cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of ANSAID in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking nonsteroidal anti-inflammatory drugs, including ANSAID. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with nonsteroidal anti-inflammatory drugs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test val- ues, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ANSAID. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), ANSAID should be discontinued. Renal effects: Caution should be used when initiating treatment with ANSAID in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with ANSAID. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS, Advanced Renal Disease). In clinical studies, the elimination half-life of flurbiprofen was unchanged in patients with renal impairment. Flurbiprofen metabolites are eliminated primarily by the kidneys. Elimination of 4’- hydroxy-flurbiprofen was reduced in patients with moderate to severe renal impairment. Therefore, patients with significantly impaired renal function may require a reduction of dosage to avoid accu- mulation of flurbiprofen metabolites. Such patients should be closely monitored (see CLINICAL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 10 PHARMACOLOGY). Hematological effects: Anemia is sometimes seen in patients receiving nonsteroidal anti-inflammatory drugs, including ANSAID. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with nonsteroidal anti-inflammatory drugs, including ANSAID, should have their hemoglobin or hematocrit checked periodically even if they do not exhibit any signs or symptoms of anemia. Nonsteroidal anti-inflammatory drugs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. ANSAID does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving ANSAID who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti- inflammatory drugs has been reported in such aspirin-sensitive patients, ANSAID should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Vision changes: Blurred and/or diminished vision has been reported with the use of ANSAID and other nonsteroidal anti-inflammatory drugs. Patients experiencing eye complaints should have ophthalmologic examinations. Information For PatientsPatients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. • ANSAID, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, CARDIOVASCULAR EFFECTS). • ANSAID, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding and Perforation). • ANSAID, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be advised to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 11 stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. • Patients should promptly report , signs or symptoms of unexplained weight gain, or edema to their physicians. • Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. • Patients should informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). In late pregnancy, as with other NSAIDs, ANSAID should be avoided because it willmay cause premature closure of the ductus arteriosus. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs of symptoms of GI bleeding. Patients on long-term treatment with non- steroidal anti-inflammatory drugs should have their CBC and chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash etc.), or abnormal liver tests persist or worsen, ANSAID should be discontinued. Drug Interactions ACE-inhibitors: Reports suggest that nonsteroidal anti-inflammatory drugs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking nonsteroidal anti- inflammatory drugs concomitantly with ACE-inhibitors. Anticoagulants: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. The physician should be cautious when administering ANSAID to patients taking warfarin or other anticoagulants. Aspirin: Concurrent administration of aspirin lowers serum flurbiprofen concentrations (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). When ANSAID is administered with aspirin, its protein binding is reduced, although the clearance of free ANSAID is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of flurbiprofen and aspirin is not generally recommended because of the potential for increased adverse effects. Beta-adrenergic blocking agents: Flurbiprofen attenuated the hypotensive effect of propranolol but not atenolol (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). The mechanism This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 12 underlying this interference is unknown. Patients taking both flurbiprofen and a beta-blocker should be monitored to ensure that a satisfactory hypotensive effect is achieved. Diuretics: Clinical studies, as well as post marketing observations, have shown that ANSAID can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see PRECAUTIONS, Renal Effects), as well as diuretic efficacy. Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the nonsteroidal anti-inflammatory drug. Thus, when nonsteroidal anti-inflammatory drugs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate: Nonsteroidal anti-inflammatory drugs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the tox- icity of methotrexate. Caution should be used when nonsteroidal anti-inflammatory drugs are administered concomitantly with methotrexate. Pregnancy: Teratogenic effects: Pregnancy Category C. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. ANSAID should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic effects: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided. Labor and Delivery In rat studies with nonsteroidal anti-inflammatory drugs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of ANSAID on labor and delivery in pregnant women are unknown. Nursing Mothers Concentrations of flurbiprofen in breast milk and plasma of nursing mothers suggest that a nursing infant could receive approximately 0.10 mg flurbiprofen per day in the established milk of a woman taking ANSAID 200 mg/day. Because of possible adverse effects of prostaglandin-inhibiting drugs on neonates, 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 13 As with any NSAID, caution should be exercised in treating the elderly (65 years and older). Clinical experience with ANSAID suggests that elderly patients may have a higher incidence of gastrointestinal complaints than younger patients, including ulceration, bleeding, flatulence, bloating, and abdominal pain. To minimize the potential risk for gastrointestinal events, the lowest effective dose should be used for the shortest possible duration (see WARNINGS, Gastrointestinal Effects). Likewise, elderly patients are at greater risk of developing renal decompensation (see PRECAUTIONSWARNINGS, Renal Effects). The pharmacokinetics of flurbiprofen do not seem to differ in elderly patients from those in younger individuals (see CLINICAL PHARMACOLOGY, Special Populations). The rate of absorption of ANSAID was reduced in elderly patients who also received antacids, although the extent of absorption was not affected (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). ADVERSE REACTIONS TABLE 2. Reported adverse events in patients receiving ANSAID or other nonsteroidal anti-inflammatory drugs Reported in patients treated with ANSAID Incidence of 1% or greater † Incidence < 1% - Causal Relationship Probable ‡ Incidence < 1% - Causal Relationship Unknown ‡ Reported in patients treated with other products but not ANSAID BODY AS A WHOLE edema anaphylactic reaction chills fever < 1%: death infection sepsis CARDIOVASCULAR SYSTEM congestive heart failure hypertension vascular diseases vasodilation angina pectoris arrhythmias myocardial infarction < 1%: hypotension palpitations syncope tachycardia vasculitis DIGESTIVE SYSTEM abdominal pain constipation diarrhea dyspepsia/heartburn elevated liver enzymes flatulence GI bleeding nausea vomiting bloody diarrhea esophageal disease gastric/peptic ulcer disease gastritis jaundice (cholestatic and noncholestatic) hematemesis hepatitis stomatitis/glossitis appetite changes cholecystitis colitis dry mouth exacerbation of inflammatory bowel disease periodontal abscess small intestine inflammation with loss of blood and protein > 1%: GI perforation GI ulcers (gastric/duodenal) < 1%: eructation liver failure pancreatitis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 14 HEMIC AND LYMPHATIC SYSTEM aplastic anemia (including agranulocytosis or pancytopenia) decrease in hemoglobin and hematocrit ecchymosis/purpura eosinophilia hemolytic anemia iron deficiency anemia leukopenia thrombocytopenia lymphadenopathy > 1%: anemia increased bleeding time < 1%: melena rectal bleeding METABOLIC AND NUTRITIONAL SYSTEM body weight changes hyperuricemia hyperkalemia < 1%: hyperglycemia NERVOUS SYSTEM headache nervousness and other manifestations of central nervous system (CNS) stimulation (eg, anxiety, insomnia, increased reflexes, tremor) symptoms associated with CNS inhibition (eg, amnesia, asthenia, depression, malaise, somnolence) ataxia cerebrovascular ischemia confusion paresthesia twitching convulsion cerebrovascular accident emotional lability hypertonia meningitis myasthenia subarachnoid hemorrhage < 1%: coma dream abnormalities drowsiness hallucinations RESPIRATORY SYSTEM rhinitis asthma epistaxis bronchitis dyspnea hyperventilation laryngitis pulmonary embolism pulmonary infarct < 1%: pneumonia respiratory depression This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 15 Reported in patients treated with ANSAID Incidence of 1% or greater † Incidence < 1% - Causal Relationship Probable ‡ Incidence < 1% - Causal Relationship Unknown ‡ Reported in patients treated with other products but not ANSAID SKIN AND APPENDAGES rash angioedema eczema exfoliative dermatitis photosensitivity pruritus toxic epidermal necrolysis urticaria alopecia dry skin herpes simplex/zoster nail disorder sweating < 1%: erythema multiforme Stevens Johnson syndrome SPECIAL SENSES changes in vision dizziness/vertigo tinnitus conjunctivitis parosmia changes in taste corneal opacity ear disease glaucoma retinal hemorrhage retrobulbar neuritis transient hearing loss > 1%: pruritus < 1%: hearing impairment UROGENITAL SYSTEM signs and symptoms suggesting urinary tract infection hematuria interstitial nephritis renal failure menstrual disturbances prostate disease vaginal and uterine hemorrhage vulvovaginitis > 1%: abnormal renal function < 1%: dysuria oliguria polyuria proteinuria † from clinical trials ‡ from clinical trials, post-marketing surveillance, or literature OVERDOSAGE Symptoms following acute overdoses with nonsteroidal anti-inflammatory drugs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of nonsteroidal anti-inflammatory drugs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following overdose with a nonsteroidal anti-inflammatory drug. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms, or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 16 DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of ANSAID and other treatment options before deciding to use ANSAID. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with ANSAID, the dose and frequency should be adjusted to suit an individual patient’s needs. For relief of the signs and symptoms of rheumatoid arthritis or osteoarthritis, the recommended starting dose of ANSAID is 200 to 300 mg per day, divided for administration two, three, or four times a day. The largest recommended single dose in a multiple-dose daily regimen is 100 mg. HOW SUPPLIED ANSAID Tablets are available as follows: 50 mg: white, oval, film-coated, imprinted ANSAID 50 mg Bottles of 2000 NDC 0009-0170-24 100 mg: blue, oval, film-coated, imprinted ANSAID 100 mg Bottles of 100 NDC 0009-0305-03 Bottles of 2000 NDC 0009-0305-30 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Pharmacia & Upjohn Company A subsidiary of Pharmacia Corporation Kalamazoo, MI 49001, USA Revised July 2005 LABXXX-XX 691439 Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non- Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 17 NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).” NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: • can happen without warning symptoms • may cause death The chance of a person getting an ulcer or bleeding increases with: • taking medicines called “corticosteroids” and “anticoagulants” • longer use • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as: • different types of arthritis • menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider: • about all your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding. Talk to your doctor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 18 What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness Get emergency help right away if you have any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-766/S-013 Page 19 Generic Name Tradename Etodolac Lodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 Flurbirofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 This Medication Guide has been approved by the U.S. Food and Drug Administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:57.030735	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018766s013lbl.pdf', 'application_number': 18766, 'submission_type': 'SUPPL ', 'submission_number': 13}
11,322	Rx only VePesid ® (etoposide) For Injection and Capsules DESCRIPTION VePesid® (etoposide) (also commonly known as VP-16) is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. It is 4'-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside]. It is very soluble in methanol and chloroform, slightly soluble in ethanol, and sparingly soluble in water and ether. It is made more miscible with water by means of organic solvents. It has a molecular weight of 588.58 and a molecular formula of C29H32O13. VePesid may be administered either intravenously or orally. VePesid For Injection is available in 100 mg (5 mL), 150 mg (7.5 mL), 500 mg (25 mL), or 1 gram (50 mL) sterile, multiple dose vials. The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol.Vial headspace contains nitrogen. VePesid is also available as 50 mg pink capsules. Each liquid filled, soft gelatin capsule contains 50 mg of etoposide in a vehicle consisting of citric acid, glycerin, purified water, and polyethylene glycol 400. The soft gelatin capsules contain gelatin, glycerin, sorbitol, purified water, and parabens (ethyl and propyl) with the following dye system: iron oxide (red) and titanium dioxide; the capsules are printed with edible ink. The structural formula is: CLINICAL PHARMACOLOGY VePesid has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, how- ever, appears to be at the G2 portion of the cell cycle in mammalian cells. Two different dose- dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA topoisomerase II or the formation of free radicals. Pharmacokinetics On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life rang- ing from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min or 16 to 36 mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a range 100-600 mg/m2. Over the same dose range, the areas under the plasma concentration vs time curves (AUC) and the maximum plasma concentration (Cmax) values increase linearly with dose. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m2 for 4 to 5 days. The mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to 17 L/m2. Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. In vitro, etoposide is highly protein bound (97%) to human plasma proteins. An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children. In a study deter- mining the effect of other therapeutic agents on the in vitro binding of carbon-14 labeled etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations achieved in vivo. Etoposide binding ratio correlates directly with serum albumin in patients with cancer and in normal volunteers. The unbound fraction of etoposide significantly correlated with bilirubin in a population of cancer patients. Data have suggested a significant inverse cor- relation between serum albumin concentration and free fraction of etoposide. (See PRE- CAUTIONS section.) After intravenous administration of 14C-etoposide (100-124 mg/m2), mean recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as etoposide; fecal recovery of radioactivity was 44% of the dose at 120 hours. In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m2 or about 35% of the total body clearance over a dose range of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. The effect of renal dis- ease on plasma etoposide clearance is not known. Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. The hydroxy acid metabolite [4'-demethylepipodophyllic acid-9-(4,6-O-(R)-ethylidene-β-D-glucopyra- noside)], formed by opening of the lactone ring, is found in the urine of adults and children. It is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14C-etoposide. In addition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol. After either intravenous infusion or oral capsule administration, the Cmax and AUC values exhibit marked intra- and inter-subject variability. This results in variability in the estimates of the absolute oral bioavailability of etoposide oral capsules. Cmax and AUC values for orally administered etoposide capsules consistently fall in the same range as the Cmax and AUC values for an intravenous dose of one-half the size of the oral dose. The overall mean value of oral capsule bioavailability is approximately 50% (range 25–75%). The bioavailability of etoposide capsules appears to be linear up to a dose of at least 250 mg/m2. There is no evidence of a first-pass effect for etoposide. For example, no correlation exists between the absolute oral bioavailability of etoposide capsules and nonrenal clear- ance. No evidence exists for any other differences in etoposide metabolism and excretion after administration of oral capsules as compared to intravenous infusion. In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration, and nonrenal clearance. Patients with impaired renal func- tion receiving etoposide have exhibited reduced total body clearance, increased AUC and a lower volume of distribution at steady state. (See PRECAUTIONS section.) Use of cisplatin ther- apy is associated with reduced total body clearance. In children, elevated serum SGPT lev- els are associated with reduced drug total body clearance. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children. Although some minor differences in pharmacokinetic parameters between age and gender have been observed, these differences were not considered clinically significant. INDICATION AND USAGE VePesid (etoposide) is indicated in the management of the following neoplasms: Refractory Testicular Tumors—VePesid For Injection in combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumors who have already received appropriate surgical, chemotherapeutic, and radiotherapeutic therapy. Adequate data on the use of VePesid Capsules in the treatment of testicular cancer are not available. Small Cell Lung Cancer—VePesid For Injection and/or Capsules in combination with other approved chemotherapeutic agents as first line treatment in patients with small cell lung cancer. CONTRAINDICATIONS VePesid is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation. WARNINGS Patients being treated with VePesid must be frequently observed for myelosuppression both during and after therapy. Myelosuppression resulting in death has been reported. Dose- limiting bone marrow suppression is the most significant toxicity associated with VePesid therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of VePesid: platelet count, hemoglobin, white blood cell count, and differential. The occurrence of a platelet count below 50,000/mm3 or an absolute neutrophil count below 500/mm3 is an indication to withhold further therapy until the blood counts have sufficiently recovered. Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. Higher rates of anaphylactic-like reactions have been reported in children who received infusions at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactic-like reactions is uncertain. (See ADVERSE REACTIONS section.) Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of pressor agents, corti- costeroids, antihistamines, or volume expanders at the discretion of the physician. For parenteral administration, VePesid should be given only by slow intravenous infusion (usually over a 30- to 60-minute period) since hypotension has been reported as a possible side effect of rapid intravenous injection. Pregnancy VePesid can cause fetal harm when administered to a pregnant woman. Etoposide has been shown to be teratogenic in mice and rats. In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 1/20th of the human dose on a mg/m2 basis) during organogenesis caused maternal toxicity, embryotoxicity, and ter- atogenicity (skeletal abnormalities, exencephaly, encephalocele, and anophthalmia); higher doses of 1.2 and 3.6 mg/kg/day (about 1/7th and 1/2 of human dose on a mg/m2 basis) resulted in 90 and 100% embryonic resorptions. In mice, a single 1.0 mg/kg (1/16th of human dose on a mg/m2 basis) dose of etoposide administered intraperitoneally on days 6, 7, or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletal mal- formations. An I.P. dose of 1.5 mg/kg (about 1/10th of human dose on a mg/m2 basis) on day 7 of gestation caused an increase in the incidence of intrauterine death and fetal mal- formations and a significant decrease in the average fetal body weight. Women of childbearing potential should be advised to avoid becoming pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be warned of the potential hazard to the fetus. VePesid should be considered a potential carcinogen in humans. The occurrence of acute leukemia with or without a preleukemic phase has been reported in rare instances in patients treated with etoposide alone or in association with other neoplastic agents. The risk of devel- opment of a preleukemic or leukemic syndrome is unclear. Carcinogenicity tests with VePesid have not been conducted in laboratory animals. PRECAUTIONS General In all instances where the use of VePesid is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of VePesid therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity. Patients with low serum albumin may be at an increased risk for etoposide associated toxicities. Drug Interactions High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone. Laboratory Tests Periodic complete blood counts should be done during the course of VePesid treatment. They should be performed prior to each cycle of therapy and at appropriate intervals during and after therapy. At least one determination should be done prior to each dose of VePesid. Renal Impairment In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance: Subsequent VePesid dosing should be based on patient tolerance and clinical effect. Data are not available in patients with creatinine clearances <15 mL/min and further dose reduction should be considered in these patients. Carcinogenesis (see WARNINGS section), Mutagenesis, Impairment of Fertility Etoposide has been shown to be mutagenic in Ames assay. Treatment of Swiss-Albino mice with 1.5 mg/kg I.P. of VePesid on day 7 of gestation increased the incidence of intrauterine death and fetal malformations as well as signifi- cantly decreased the average fetal body weight. Maternal weight gain was not affected. Irreversible testicular atrophy was present in rats treated with etoposide intravenously for 30 days at 0.5 mg/kg/day (about 1/16th of the human dose on a mg/m2 basis). Pregnancy Pregnancy “Category D.” (See WARNINGS section.) Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excret- ed in human milk and because of the potential for serious adverse reactions in nursing infants from VePesid, 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. VePesid (etoposide) For Injection contains polysorbate 80. In premature infants, a life- threatening syndrome consisting of liver and renal failure, pulmonary deterioration, thrombocy- topenia, and ascites has been associated with an injectable vitamin E product containing polysorbate 80. Anaphylactic reactions have been reported in pediatric patients. (See WARNINGS section.) Geriatric Use Clinical studies of VePesid (etoposide) for the treatment of refractory testicular tumors did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Of more than 600 patients in four clinical studies in the NDA databases who received VePesid or etoposide phosphate in combination with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC), about one third were older than 65 years. When advanced age was determined to be a prog- nostic factor for response or survival in these studies, comparisons between treatment groups were performed for the elderly subset. In the one study (etoposide in combination Measured Creatinine Clearance >50 mL/min 15-50 mL/min etoposide 100% of dose 75% of dose WARNINGS VePesid (etoposide) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe myelosuppression with resulting infection or bleeding may occur. F.P.O. with cyclophosphamide and vincristine compared with cyclophosphamide and vincristine or cyclophosphamide, vincristine, and doxorubicin) where age was a significant prognostic fac- tor for survival, a survival benefit for elderly patients was observed for the etoposide regimen compared with the control regimens. No differences in myelosuppression were seen between elderly and younger patients in these studies except for an increased frequency of WHO Grade III or IV leukopenia among elderly patients in a study of etoposide phosphate or etoposide in com- bination with cisplatin. Elderly patients in this study also had more anorexia, mucositis, dehy- dration, somnolence, and elevated BUN levels than younger patients. In five single-agent studies of etoposide phosphate in patients with a variety of tumor types, 34% of patients were age 65 years or more. WHO Grade III or IV leukopenia, granulocytope- nia, and asthenia were more frequent among elderly patients. Postmarketing experience also suggests that elderly patients may be more sensitive to some of the known adverse effects of etoposide, including myelosuppression, gastrointestinal effects, infectious complications, and alopecia. Although some minor differences in pharmacokinetic parameters between elderly and nonelderly patients have been observed, these differences were not considered clinically sig- nificant. Etoposide and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse 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 PRECAUTIONS: Renal Impairment for recommended dosing adjustments in patients with renal impairment). ADVERSE REACTIONS The following data on adverse reactions are based on both oral and intravenous administra- tion of VePesid (etoposide) as a single agent, using several different dose schedules for treat- ment of a wide variety of malignancies. Hematologic Toxicity Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after drug admin- istration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Fever and infection have also been reported in patients with neutropenia. Death associated with myelosuppression has been reported. The occurrence of acute leukemia with or without a preleukemic phase has been reported rarely in patients treated with VePesid in association with other antineoplastic agents. (See WARNINGS section.) Gastrointestinal Toxicity Nausea and vomiting are the major gastrointestinal toxicities. The severity of such nausea and vomiting is generally mild to moderate with treatment discontinuation required in 1% of patients. Nausea and vomiting can usually be controlled with standard antiemetic therapy. Mild to severe mucositis/esophagitis may occur. Gastrointestinal toxicities are slightly more frequent after oral administration than after intravenous infusion. Hypotension Transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients. It has not been associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has been noted. To prevent this rare occurrence, it is recom- mended that VePesid be administered by slow intravenous infusion over a 30- to 60-minute period. If hypotension occurs, it usually responds to cessation of the infusion and administra- tion of fluids or other supportive therapy as appropriate. When restarting the infusion, a slower administration rate should be used. Allergic Reactions Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dysp- nea, and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving intravenous VePesid and in less than 1% of the patients treated with the oral capsules. These reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as appropriate; how- ever, the reactions can be fatal. Hypertension and/or flushing have also been reported. Blood pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic- like reactions have occurred during the initial infusion of VePesid. Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain, and/or loss of consciousness have sometimes occurred in association with the above reactions. In addition, an apparent hypersensitivity-associated apnea has been reported rarely. Rash, urticaria, and/or pruritus have infrequently been reported at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported. Alopecia Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66% of patients. Other Toxicities The following adverse reactions have been infrequently reported: abdominal pain, aftertaste, constipation, dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness, optic neuritis, interstitial pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associ- ated with allergic reactions), Stevens-Johnson syndrome, and toxic epidermal necrolysis, pig- mentation, and a single report of radiation recall dermatitis. Hepatic toxicity, generally in patients receiving higher doses of the drug than those recom- mended, has been reported with VePesid. Metabolic acidosis has also been reported in patients receiving higher doses. Reports of extravasation with swelling have been received postmarketing. Rarely extrava- sation has been associated with necrosis and venous induration. The incidences of adverse reactions in the table that follows are derived from multiple data bases from studies in 2,081 patients when VePesid was used either orally or by injection as a single agent. OVERDOSAGE No proven antidotes have been established for VePesid overdosage. DOSAGE AND ADMINISTRATION Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, buta- diene, and styrene) have been reported to crack and leak when used with undiluted VePesid For Injection. VePesid For Injection The usual dose of VePesid For Injection in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m2/day on days 1 through 5 to 100 mg/m2/day on days 1, 3, and 5. In small cell lung cancer, the VePesid For Injection dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m2/day for 4 days to 50 mg/m2/day for 5 days. For recommended dosing adjustments in patients with renal impairment see PRECAU- TIONS section. Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from any toxicity. PERCENT RANGE OF ADVERSE DRUG EFFECT REPORTED INCIDENCE Hematologic toxicity Leukopenia (less than 1,000 WBC/mm3) 3–17 Leukopenia (less than 4,000 WBC/mm3) 60–91 Thrombocytopenia (less than 50,000 platelets/mm3) 1–20 Thrombocytopenia (less than 100,000 platelets/mm3) 22–41 Anemia 0–33 Gastrointestinal toxicity Nausea and vomiting 31–43 Abdominal pain 0–20 Anorexia 10–13 Diarrhea 1–13 Stomatitis 1–60 Hepatic 0–30 Alopecia 8–66 Peripheral neurotoxicity 1–20 Hypotension 1–20 Allergic reaction 1–20 VePesid Capsules In small cell lung cancer, the recommended dose of VePesid Capsules is two times the IV dose rounded to the nearest 50 mg. The dosage, by either route, should be modified to take into account the myelosuppres- sive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve. Administration Precautions As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of VePesid. Skin reactions associated with accidental exposure to VePesid may occur. The use of gloves is recommended. If VePesid solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water. Preparation for Intravenous Administration VePesid For Injection must be diluted prior to use with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur. Hypotension following rapid intravenous administration has been reported, hence, it is rec- ommended that the VePesid solution be administered over a 30- to 60-minute period. A longer duration of administration may be used if the volume of fluid to be infused is a con- cern. VePesid should not be given by rapid intravenous injection. Parenteral drug products should be inspected visually for particulate matter and discoloration (see DESCRIPTION section) prior to administration whenever solution and container permit. Stability Unopened vials of VePesid For Injection are stable for 24 months at room temperature (25° C). Vials diluted as recommended to a concentration of 0.2 to 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature (25° C) under normal room fluorescent light in both glass and plastic containers. VePesid Capsules must be stored under refrigeration 2°–8° C (36°–46° F). The capsules are stable for 24 months under such refrigeration conditions. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. HOW SUPPLIED VePesid® (etoposide) For Injection NDC 0015-3095-20—100 mg/5 mL Sterile, Multiple Dose Vial, 10’s NDC 0015-3084-20—150 mg/7.5 mL Sterile, Multiple Dose Vial NDC 0015-3061-20—500 mg/25 mL Sterile, Multiple Dose Vial NDC 0015-3062-20—1 gram/50 mL Sterile, Multiple Dose Vial VePesid® (etoposide) Capsules NDC 0015-3091-45—50 mg pink capsules with “BRISTOL 3091” printed in black in blis- terpacks of 20 individually labeled blisters, each containing one capsule. Capsules are to be stored under refrigeration 2°–8° C (36°–46° F). DO NOT FREEZE. Dispense in child-resistant containers. For information on package sizes available, refer to the current price schedule. References 1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommen- dations for Practice Pittsburgh, PA: Oncology Nursing Society; 1999:32-41. 2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. US Dept of Health and Human Services, Public Health Service publication NIH 83-2621. 3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591. 4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cyto- toxic 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. 5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428. 6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA–A Cancer J for Clin. 1983;33:258-263. 7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on han- dling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. 8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.). Am J Health-SystPharm. 1996;53:1669-1685. Capsules: Injection: Manufactured by: R.P. Scherer GmbH Eberback/Baden, Germany Bristol-Myers Squibb Co. Princeton, New Jersey 08543 USA Distributed by: Bristol-Myers Squibb Co. Princeton, New Jersey 08543 USA 51-001106-05 Revised November 2004 Item 2 Vol 1 Page 018 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:57.231754	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/019557s028lbl.pdf', 'application_number': 18768, 'submission_type': 'SUPPL ', 'submission_number': 45}
11,321	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ANSAID safely and effectively. See full prescribing information for ANSAID. ANSAID (flurbiprofen) tablet, for oral use Initial U.S. Approval: 1988 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning.  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (Error! Reference source not found.)  ANSAID is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (Error! Reference source not found., 5.1)  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (Error! Reference source not found.) RECENT MAJOR CHANGES Boxed Warning 5/2016 Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 5/2016 Warnings and Precautions, Heart Failure and Edema (5.5) 5/2016 INDICATIONS AND USAGE ANSAID is a nonsteroidal anti-inflammatory drug indicated for  Relief of the signs and symptoms of rheumatoid arthritis  Relief of the signs and symptoms of osteoarthritis DOSAGE AND ADMINISTRATION  Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2)  The recommended starting dose of ANSAID is 200 to 300 mg per day, divided for administration two, three, or four times a day. The largest recommended single dose in a multiple-dose daily regimen is 100 mg (2) DOSAGE FORMS AND STRENGTHS ANSAID (flurbiprofen) tablet: 50 mg and 100 mg (3) CONTRAINDICATIONS  Known hypersensitivity to flurbiprofen or any components of the drug product (Error! Reference source not found.)  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (Error! Reference source not found.)  In the setting of CABG surgery (Error! Reference source not found.) WARNINGS AND PRECAUTIONS  Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (Error! Reference source not found.)  Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (0, 7)  Heart Failure and Edema: Avoid use of ANSAID in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (0)  Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ANSAID in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (0)  Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (0)  Exacerbation of Asthma Related to Aspirin Sensitivity: ANSAID is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (Error! Reference source not found.)  Serious Skin Reactions: Discontinue ANSAID at first appearance of skin rash or other signs of hypersensitivity (5.9)  Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30 weeks gestation. (5.10, 8.1)  Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.11, 7) ADVERSE REACTIONS Most common adverse reactions (incidence > 3% from clinical trials) are: abdominal pain, dyspepsia, nausea, diarrhea, constipation, headache, edema, signs and symptoms suggesting urinary tract infection (Error! Reference source not found.) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1 800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS  Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking ANSAID with drugs that interfere with hemostasis. Concomitant use of ANSAID and analgesic doses of aspirin is not generally recommended (7)  ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with ANSAID may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7)  ACE Inhibitors and ARBs: Concomitant use with ANSAID in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7)  Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) USE IN SPECIFIC POPULATIONS Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1) Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of ANSAID in women who have difficulties conceiving (8.3) See 0 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 5/2016 Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Premature Closure of Fetal Ductus Arteriosus 5.11 Hematologic Toxicity 5.12 Masking of Inflammation and Fever 5.13 Laboratory Monitoring 5.14 Vision Changes 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 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 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 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3928083 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: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)].  ANSAID is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE ANSAID is indicated:  For relief of the signs and symptoms of rheumatoid arthritis.  For relief of the signs and symptoms of osteoarthritis. 2 DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of ANSAID and other treatment options before deciding to use ANSAID. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with ANSAID, the dose and frequency should be adjusted to suit an individual patient’s needs. For relief of the signs and symptoms of rheumatoid arthritis or osteoarthritis, the dosage is 200 to 300 mg per day, divided for administration two, three, or four times a day. The largest recommended single dose in a multiple-dose daily regimen is 100 mg. 3 DOSAGE FORMS AND STRENGTHS ANSAID (Flurbiprofen) tablets: 50 mg white, oval, film-coated, imprinted ANSAID 50 mg 100 mg blue, oval, film-coated, imprinted ANSAID 100 mg Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 CONTRAINDICATIONS ANSAID is contraindicated in the following patients:  Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to flurbiprofen or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to nonsteroidal anti-inflammatory drugs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)].  In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as flurbiprofen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Avoid the use of ANSAID in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ANSAID is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including ANSAID, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-times increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients:  Use the lowest effective dosage for the shortest possible duration.  Avoid administration of more than one NSAID at a time.  Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.  Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.  If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue ANSAID until a serious GI adverse event is ruled out.  In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including flurbiprofen. Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue ANSAID immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including ANSAID, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (Error! Reference source not found.7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of flurbiprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of ANSAID in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ANSAID is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. In clinical studies, the elimination half-life of flurbiprofen was unchanged in patients with renal impairment. Flurbiprofen metabolites are eliminated primarily by the kidneys. Elimination of 4’ hydroxy-flurbiprofen was reduced in patients with moderate to severe renal impairment. Therefore, treatment with ANSAID is not recommended in these patients with advanced renal disease. If Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ANSAID therapy must be initiated, close monitoring of the patients renal function is advisable [see Clinical Pharmacology (12)]. Correct volume status in dehydrated or hypovolemic patients prior to initiating ANSAID. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of ANSAID [see Drug Interactions (7)]. Avoid the use of ANSAID in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If ANSAID is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Flurbiprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to flurbiprofen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, ANSAID is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When ANSAID is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including flurbiprofen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of ANSAID at the first appearance of skin rash or any other sign of hypersensitivity. ANSAID is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Premature Closure of Fetal Ductus Arteriosus Flurbiprofen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including ANSAID, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations (8.1)]. 5.11 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with ANSAID has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NSAIDs, including ANSAID, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders of concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.12 Masking of Inflammation and Fever The pharmacological activity of ANSAID in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.13 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.30,5.6)]. 5.14 Vision changes Blurred and/or diminished vision has been reported with the use of ANSAID and other nonsteroidal anti-inflammatory drugs. Patients experiencing eye complaints should have ophthalmologic examinations. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:  Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]  GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]  Hepatotoxicity [see Warnings and Precautions (5.3)]  Hypertension [see Warnings and Precautions (5.4)]  Heart Failure and Edema [see Warnings and Precautions (5.5)]  Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]  Anaphylactic Reactions [see Warnings and Precautions (5.7)]  Serious Skin Reactions [see Warnings and Precautions (5.9)]  Hematologic Toxicity [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Incidence of 1% or greater Body as a whole: edema Digestive system: GI bleeding, abdominal pain, constipation, diarrhea, dyspepsia/heartburn, flatulence, nausea, vomiting, elevated liver enzymes Metabolic and nutritional system: body weight changes Nervous system: headache, nervousness, anxiety, insomnia, increased reflexes, tremor, amnesia, asthenia, depression, malaise, somnolence Respiratory system: rhinitis Skin and appendages: rash Special senses: changes in vision, dizziness, tinnitus Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Urogenital system: signs and symptoms suggesting urinary tract infection Incidence < 1% Body as a whole: anaphylactic reaction, chills, fever Cardiovascular system: myocardial infarction, congestive heart failure, hypertension, vascular diseases, vasodilation Digestive system: gastric/peptic ulcer disease, hematemesis, bloody diarrhea, hepatitis, esophageal disease, gastritis, stomatitis/glossitis, dry mouth Hemic and lymphatic system: iron deficiency anemia, decrease in hemoglobin and hematocrit, purpura, eosinophilia Metabolic and nutritional system: hyperuricemia Nervous system: cerebrovascular ischemia, convulsion, ataxia, confusion, hypertonia, paresthesia, twitching, emotional lability Respiratory system: asthma, dyspnea, epistaxis, bronchitis, laryngitis Skin and appendages: angioedema, urticaria, eczema, pruritus, herpes simplex, alopecia, dry skin Special senses: vertigo, corneal opacity, parosmia, conjunctivitis Urogenital system: renal failure, vaginal hemorrhage, hematuria 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ANSAID. 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. Cardiovascular system: angina pectoris, arrhythmias Digestive system: jaundice (cholestatic and noncholestatic), colitis, small intestine inflammation with loss of blood and protein, exacerbation of inflammatory bowel disease, cholecystitis, periodontal abscess, appetite changes Hemic and lymphatic system: aplastic anemia (including agranulocytosis or pancytopenia), hemolytic anemia, leukopenia, thrombocytopenia, ecchymosis, lymphadenopathy Metabolic and nutritional system: hyperkalemia Nervous system: cerebrovascular accident, subarachnoid hemorrhage, meningitis, myasthenia Respiratory system: pulmonary infarct, pulmonary embolism, hyperventilation, Skin and appendages: toxic epidermal necrolysis, exfoliative dermatitis, zoster, photosensitivity, nail disorder, sweating Special senses: retinal hemorrhage, glaucoma, retrobulbar neuritis, transient hearing loss, changes in taste, ear disease Urogenital system: interstitial nephritis, uterine hemorrhage, menstrual disturbances, prostate disease, vulvovaginitis Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Drug Interactions See Table 1 for clinically significant drug interactions with flurbiprofen. Table 1: Clinically Significant Drug Interactions with Flurbiprofen Drugs That Interfere with Hemostasis Clinical Impact:  Flurbiprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of flurbiprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.  Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of ANSAID with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (0)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (Error! Reference source not found.)]. Concurrent administration of aspirin lowers serum flurbiprofen concentrations. The clinical significance of this interaction is not known. Intervention: Concomitant use of ANSAID and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (0)]. ANSAID is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact:  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol).  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Intervention:  During concomitant use of ANSAID and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  During concomitant use of ANSAID and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].  When drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ANSAID with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (0)]. Digoxin Clinical Impact: The concomitant use of flurbiprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin [see Clinical Pharmacology (12.3)]. Intervention: During concomitant use of ANSAID and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ANSAID and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of ANSAID and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of ANSAID and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of ANSAID and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of flurbiprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of flurbiprofen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of ANSAID and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Intervention: During concomitant use of ANSAID and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with ANSAID may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of ANSAID with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)]. 8 Use in Specific Populations 8.1 Pregnancy Risk Summary Use of NSAIDs, including ANSAID, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including ANSAID, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of ANSAID in pregnant women. Data from observational studies regarding potential embryo-fetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies, delayed parturition, prolonged labor, stillborn fetuses, and the presence of retained fetuses at necropsy occurred following treatment of pregnant rats treated with oral flurbiprofen throughout gestation until labor at less than 1-time the human dose of 300 mg/day. Embryofetal lethality was seen in pregnant rats and rabbits administered oral flurbiprofen during the period of organogenesis at exposures 0.03-times and 0.5 times, respectively, the human dose of 300 mg. No evidence of malformations were noted in rats, rabbits, or mice treated with flurbiprofen during the period of organogenesis at doses that were 0.8-, 0.5-, and 0.2-times the maximum human daily dose [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as flurbiprofen, resulted in increased pre- and post-implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of ANSAID during labor or delivery. In animal studies, NSAIDS, including flurbiprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Data Animal data Pregnant rats were treated with oral doses of 0.05, 1, and 3 mg/kg flurbiprofen 14 days prior to mating through Gestation Day (GD) 16. Embryofetal lethality was seen at 1 mg/kg and above (0.03 times the maximum recommended human dose [MRHD] of 300 mg on a mg/m2 basis). No maternal toxicity was evident at this dose. No malformations were seen in fetuses from pregnant rats administered flurbiprofen during the period of organogenesis at doses up to 25 mg/kg (0.8 times the MRHD on a mg/m2 basis). Maternal toxicity (uterine hemorrhage, gastric ulcers) was observed at this dose. Pregnant rabbits were administered oral doses of 0.675, 2.25, and 7.5 mg/kg flurbiprofen from GD 1 through GD 29. Embryofetal lethality, but no evidence of teratogenicity, was seen at 7.5 mg/kg (0.5 times the MRHD of 300 mg on a mg/m2 basis). Maternal toxicity (gastric ulcers and lethality) was observed at this dose. Pregnant mice were treated with oral doses of 2, 5, and 12 mg/kg flurbiprofen from GD 3 to 18. An increased incidence of fetal lethality occurred in the 12 mg/kg group (0.2 times the MRHD). All doses were associated with some evidence of maternal toxicity (placental hemorrhage). Pregnant rats were treated with oral doses of 0.2, 0.675, 2.25, 7.5, and 25 mg/kg flurbiprofen from GD 1 until labor. Delayed delivery, the incidence of stillborn pups, and decreased pup viability, were noted at doses of 2.25 mg/kg and higher (0.07 times the MRHD). These doses were associated with maternal toxicity (uterine hemorrhage, gastrointestinal ulceration, decreased body weight). Pregnant rats treated with oral doses of 0.4, 4, and 10 mg/kg flurbiprofen from GD 16 to labor, delayed parturition was seen at 0.4 mg/kg and above and stillborn pups were seen at 4 mg/kg and above (0.01-times and 0.13 times, respectively, the MRHD on mg/m2 basis). Uterine hemorrhage, ulceration, and mortality were noted in dams at 0.4 mg/kg and above. 8.2 Lactation Risk Summary Flurbiprofen is poorly excreted into human milk. The nursing infant dose is predicted to be approximately 0.1 mg/day in the established milk of a woman taking ANSAID 200 mg/day. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ANSAID and any potential adverse effects on the breastfed infant from ANSAID or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including ANSAID, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including ANSAID, in women who have difficulties conceiving or who are undergoing investigation of infertility. Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222 1222). 11 DESCRIPTION ANSAID (flurbiprofen) Tablets is a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drug, available as 50 mg white, oval, film-coated, imprinted ANSAID 50 mg, and 100 mg blue, oval, film-coated, imprinted ANSAID 100 mg tablets for oral administration. Flurbiprofen is a racemic mixture of (+)S- and (-)R- enantiomers. Flurbiprofen is a white or slightly yellow crystalline powder. It is slightly soluble in water at pH 7.0 and readily soluble in most polar solvents. The chemical name is [1,1’-biphenyl]-4-acetic acid, 2-fluoro-alpha-methyl-, (±)-. The molecular weight is 244.26. Its molecular formula is C15H13FO2 and it has the following structural formula: structural formula The inactive ingredients in ANSAID (both strengths) include: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, and titanium dioxide. In addition, the 100 mg tablet contains FD&C Blue No. 2. Reference ID: 3928083 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 Flurbiprofen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of ANSAID, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Flurbiprofen is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Flurbiprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because flurbiprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics General pharmacokinetic characteristics The pharmacokinetics of flurbiprofen have been characterized in healthy subjects, special populations and patients (see Table 2). The pharmacokinetics of flurbiprofen are linear, and there is little accumulation of flurbiprofen following multiple doses of ANSAID. Table 2: Mean (SD) R-, S-Flurbiprofen Pharmacokinetic Parameters Normalized to a 100 mg Dose of ANSAID Pharmacokinetic Parameter Normal Healthy Adults* (18 to 40 years) N=15 Geriatric Arthritis Patients† (65 to 83 years) N=13 End Stage Renal Disease Patients* (23 to 42 years) N=8 Alcoholic Cirrhosis Patients‡ (31 to 61 years) N=8 Peak Concentration (µg/mL) 14 (4) 16 (5) 9§ 9§ Time to Reach Peak Concentration (h) 1.9 (1.5) 2.2 (3) 2.3§ 1.2§ Urinary Recovery of Unchanged Flurbiprofen (% of Dose) 2.9 (1.3) 0.6 (0.6) 0.02 (0.02) NA║ Area Under the Curve (AUC)¶ (µg·h/mL) 83 (20) 77 (24) 44§ 50§ Apparent Volume of Distribution (Vz/F, L) 14 (3) 12 (5) 10§ 14§ Terminal Elimination Half-life (t½, h) 7.5 (0.8) 5.8 (1.9) 3.3# 5.4# *100 mg single-dose † Steady-state evaluation of 100 mg every 12 hours ‡ 200 mg single-dose § Calculated from mean parameter values of both flurbiprofen enantiomers ║ Not available ¶ AUC from 0 to infinity for single doses and from 0 to the end of the dosing interval for multiple-doses # Value for S-flurbiprofen Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Absorption The mean oral bioavailability of flurbiprofen from ANSAID tablets 100 mg is 96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed from ANSAID, with peak plasma concentrations occurring at approximately 2 hours (see Table 2). Administration of ANSAID with either food or antacids may alter the rate but not the extent of flurbiprofen absorption. Ranitidine has been shown to have no effect on either the rate or extent of flurbiprofen absorption from ANSAID. Distribution The apparent volume of distribution (Vz/F) of both R- and S-flurbiprofen is approximately 0.12 L/kg. Both flurbiprofen enantiomers are more than 99% bound to plasma proteins, primarily albumin. Plasma protein binding is relatively constant for the typical average steady-state concentrations (≤10 µg/mL) achieved with recommended doses. Flurbiprofen is poorly excreted into human milk. The nursing infant dose is predicted to be approximately 0.1 mg/day in the established milk of a woman taking ANSAID 200 mg/day. Metabolism Several flurbiprofen metabolites have been identified in human plasma and urine. These metabolites include 4’-hydroxy-flurbiprofen, 3’, 4’-dihydroxy-flurbiprofen, 3’-hydroxy-4’-methoxy-flurbiprofen, their conjugates, and conjugated flurbiprofen. Unlike other arylpropionic acid derivatives (e.g., ibuprofen), metabolism of R-flurbiprofen to S-flurbiprofen is minimal. In vitro studies have demonstrated that cytochrome CYP2C9 plays an important role in the metabolism of flurbiprofen to its major metabolite 4’-hydroxy-flurbiprofen. The 4’-hydroxy-flurbiprofen metabolite showed little anti-inflammatory activity in animal models of inflammation. In vitro studies also demonstrated glucuronidation of both enantiomers of flurbiprofen and 4’-hydroxy-flurbiprofen. UGT2B7 is the predominant UGT isozyme responsible for the glucuronidation. Flurbiprofen does not induce enzymes that alter its metabolism. Excretion Following dosing with ANSAID, less than 3% of flurbiprofen is excreted unchanged in the urine, with about 70% of the dose eliminated in the urine as flurbiprofen, 4’-hydroxy-flurbiprofen, and their acyl glucuronide conjugates. Because renal elimination is a significant pathway of elimination of flurbiprofen metabolites, dosing adjustment in patients with moderate or severe renal dysfunction may be necessary to avoid accumulation of flurbiprofen metabolites. The mean terminal elimination half-lives (t½) of R- and S-flurbiprofen are similar, about 4.7 and 5.7 hours, respectively. Specific Populations Pediatric: The pharmacokinetics of flurbiprofen have not been investigated in pediatric patients. Race: No pharmacokinetic differences due to race have been identified. Geriatric: Flurbiprofen pharmacokinetics were similar in geriatric arthritis patients, younger arthritis patients, and young healthy volunteers receiving ANSAID 100 mg as either single or multiple doses. Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatic Impairment: Hepatic metabolism may account for >90% of flurbiprofen elimination, so patients with hepatic disease may require reduced doses of ANSAID compared to patients with normal hepatic function. The pharmacokinetics of R- and S-flurbiprofen were similar, however, in alcoholic cirrhosis patients (N=8) and young healthy volunteers (N=8) following administration of a single 200 mg dose of ANSAID. Flurbiprofen plasma protein binding may be decreased in patients with liver disease and serum albumin concentrations below 3.1 g/dL. Renal Impairment: Renal clearance is an important route of elimination for flurbiprofen metabolites, but a minor route of elimination for unchanged flurbiprofen (≤3% of total clearance). The unbound clearances of R- and S-flurbiprofen did not differ significantly between normal healthy volunteers (N=6, 50 mg single dose) and patients with renal impairment (N=8, inulin clearances ranging from 11 to 43 mL/min, 50 mg multiple doses). Flurbiprofen plasma protein binding may be decreased in patients with renal impairment and serum albumin concentrations below 3.9 g/dL. Elimination of flurbiprofen metabolites may be reduced in patients with renal impairment. Flurbiprofen is not significantly removed from the blood into dialysate in patients undergoing continuous ambulatory peritoneal dialysis. Drug Interaction Studies Antacids: Administration of ANSAID to volunteers under fasting conditions or with antacid suspension yielded similar serum flurbiprofen-time profiles in young adult subjects (n=12). In geriatric subjects (n=7), there was a reduction in the rate but not the extent of flurbiprofen absorption. Aspirin: Concurrent administration of ANSAID and aspirin resulted in 50% lower serum flurbiprofen concentrations. This effect of aspirin (which is also seen with other NSAIDs) has been demonstrated in patients with rheumatoid arthritis (n=15) and in healthy volunteers (n=16) [see Drug Interactions (7)]. Beta-adrenergic Blocking Agents: The effect of flurbiprofen on blood pressure response to propra nolol and atenolol was evaluated in men with mild uncomplicated hypertension (n=10). Flurbiprofen pretreatment attenuated the hypotensive effect of a single dose of propranolol but not atenolol. Flurbiprofen did not appear to affect the beta-blocker-mediated reduction in heart rate. Flurbiprofen did not affect the pharmacokinetic profile of either drug [see Drug Interactions (7)]. Cimetidine, Ranitidine: In normal volunteers (n=9), pretreatment with cimetidine or ranitidine did not affect flurbiprofen pharmacokinetics, except for a small (13%) but statistically significant increase in the area under the serum concentration curve of flurbiprofen in subjects who received cimetidine. Digoxin: In studies of healthy males (n=14), concomitant administration of flurbiprofen and digoxin did not change the steady state serum levels of either drug [see Drug Interactions (7)]. Diuretics: Studies in healthy volunteers have shown that, like other NSAIDs, flurbiprofen can interfere with the effects of furosemide. Although results have varied from study to study, effects have been shown on furosemide-stimulated diuresis, natriuresis, and kaliuresis [see Drug Interactions (7)]. Lithium: In a study of 11 women with bipolar disorder receiving lithium carbonate at a dosage of 600 to 1200 mg/day, administration of 100 mg ANSAID every 12 hours increased plasma lithium concentrations by 19%. Four of 11 patients experienced a clinically important increase (>25% or >0.2 mmol/L) [see Drug Interactions (7)]. Methotrexate: In a study of six adult arthritis patients, coadministration of methotrexate (10 to 25 mg/dose) and ANSAID (300 mg/day) resulted in no observable interaction between these two drugs [see Drug Interactions (7)]. Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Oral Hypoglycemic Agents: In a clinical study, flurbiprofen was administered to adult diabetics who were already receiving glyburide (n=4), metformin (n=2), chlorpropamide with phenformin (n=3), or glyburide with phenformin (n=6). Although there was a slight reduction in blood sugar concentrations during concomitant administration of flurbiprofen and hypoglycemic agents, there were no signs or symptoms of hypoglycemia. Poor Metabolizers of CYP2C9 Substrates: In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin), reduce the dose of flurbiprofen to avoid abnormally high plasma levels due to reduced metabolic clearance. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Flurbiprofen was not carcinogenic in long-term studies in Fischer-344 and CD rats at doses up to 5 mg/kg/day and in CFLP mice at doses up to 12 mg/kg/day (0.16-times and 0.19-times, respectively, the human dose of 300 mg/day on a mg/m2 basis). Mutagenesis Flurbiprofen was not genotoxic in an in vivo micronucleus assay in rats. Impairment of Fertility No effect on male or female fertility in rats was observed after oral administration of 3 mg/kg flurbiprofen for 65 days prior to mating in males and 14 days prior to mating through Gestation Day 16 in females (equivalent to 0.1-times the human dose of 300 mg/day on a mg/m2 basis). This dose was not associated with significant toxicity in the dams or sires. 16 HOW SUPPLIED/STORAGE AND HANDLING ANSAID (flurbiprofen) 50 mg tablets are white, oval, film-coated, imprinted “ANSAID 50 mg” on one side, supplied as: Bottles of 2000 NDC 0009-0170-24 ANSAID (flurbiprofen) 100 mg tablets are blue, oval, film-coated, imprinted “ANSAID 100 mg” on one side, supplied as: Bottles of 100 NDC 0009-0305-03 Bottles of 2000 NDC 0009-0305-30 Store at controlled room temperature 20° to 25°C (68° to 77°F) excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with ANSAID and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda health care provider immediately [see Warnings and Precautions (Error! Reference source not found.)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (Error! Reference source not found.)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop ANSAID and seek immediate medical therapy [see Warnings and Precautions (0)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (0)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (Error! Reference source not found.) and Warnings and Precautions (0)]. Serious Skin Reactions Advise patients to stop ANSAID immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions (0)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including ANSAID, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of ANSAID and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (0) and Use in Specific Populations (0)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of ANSAID with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (Error! Reference source not found.) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with ANSAID until they talk to their healthcare provider [see Drug Interactions (7)]. Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo LAB-0104-11.x Issued May 2016 Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including:  Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.  Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs” or “SNRIs” o increasing doses of NSAIDs o longer use of NSAIDs o smoking o drinking alcohol o older age o poor health o advanced liver disease o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Reference ID: 3928083 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 NSAIDs? Do not take NSAIDs:  if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.  right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you:  have liver or kidney problems  have high blood pressure  have asthma  are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.  are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?  new or worse high blood pressure  heart failure  liver problems including liver failure  kidney problems including kidney failure  low red blood cells (anemia)  life-threatening skin reactions  life-threatening allergic reactions  Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms:  shortness of breath or trouble breathing  slurred speech  chest pain  swelling of the face or throat  weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:  nausea  vomit blood  more tired or weaker than usual  there is blood in your bowel  diarrhea movement or it is black and sticky  itching like tar  your skin or eyes look yellow  unusual weight gain Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  indigestion or stomach pain  flu-like symptoms  skin rash or blisters with fever  swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800 FDA-1088. Other information about NSAIDs  Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.  Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Pfizer Inc., 235 East 42nd Street, New York, NY, 10017 Distributed by: Pharmacia & Upjohn Company, Division of Pfizer Inc., 235 East 42nd Street, New York, NY, 10017 For more information, go to www.pfizer.com or call 1-800-438-1985 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: May 2016 LAB: 0609-1.x Reference ID: 3928083 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:57.303366	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018766s020lbl.pdf', 'application_number': 18766, 'submission_type': 'SUPPL ', 'submission_number': 20}
11,326	1 PA 3052 AMP 1 INFORMATION FOR THE PHYSICIAN 2 HUMULIN® R 3 REGULAR 4 U-500 (CONCENTRATED) 5 INSULIN HUMAN INJECTION, USP 6 (rDNA ORIGIN) 7 DESCRIPTION 8 Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia 9 coli bacteria that has been genetically altered by the addition of the gene for human insulin 10 production. Humulin R (U-500) consists of zinc-insulin crystals dissolved in a clear fluid. 11 Humulin R (U-500) is a sterile solution and is for subcutaneous injection. It should not be used 12 intravenously or intramuscularly. The concentration of Humulin R (U-500) is 500 units/mL. 13 Each milliliter contains 500 units of biosynthetic human insulin, 16 mg glycerin, 2.5 mg 14 Metacresol as a preservative, and zinc-oxide calculated to supplement endogenous zinc to obtain 15 a total zinc content of 0.017 mg/100 units. Sodium hydroxide and/or hydrochloric acid may be 16 added during manufacture to adjust the pH. 17 CLINICAL PHARMACOLOGY 18 Adequate insulin dosage permits the diabetic patient to utilize carbohydrates and fats in a 19 comparatively satisfactory manner. Regardless of concentration, the action of insulin is basically 20 the same: to enable carbohydrate metabolism to occur and thus to prevent the production of 21 ketone bodies by the liver. Although, under usual circumstances, diabetes can be controlled with 22 doses in the vicinity of 40 to 60 units or less, an occasional patient develops such resistance or 23 becomes so unresponsive to the effect of insulin that daily doses of several hundred, or even 24 several thousand, units are required. Patients who require doses in excess of 300 to 500 units 25 daily usually have impaired insulin receptor function. 26 Occasionally, a cause of the insulin resistance can be found (such as hemochromatosis, 27 cirrhosis of the liver, some complicating disease of the endocrine glands other than the pancreas, 28 allergy, or infection), but in other cases, no cause of the high insulin requirement can be 29 determined. 30 Humulin R (U-500) is unmodified by any agent that might prolong its action; however, clinical 31 experience has shown that it frequently has a time action similar to a repository insulin 32 preparation. It takes effect rapidly but has a relatively long duration of activity following a single 33 dose (up to 24 hours) as compared with other Regular insulins. This effect has been credited to 34 the high concentration of the preparation. The time course of action of any insulin may vary 35 considerably in different individuals or at different times in the same individual. As with all 36 insulin preparations, the duration of action of Humulin R (U-500) is dependent on dose, site of 37 injection, blood supply, temperature, and physical activity. 38 INDICATIONS AND USAGE 39 Humulin R (U-500) is especially useful for the treatment of diabetic patients with marked 40 insulin resistance (daily requirements more than 200 units), since a large dose may be 41 administered subcutaneously in a reasonable volume. 42 CONTRAINDICATIONS 43 Humulin R (U-500) is contraindicated in hypoglycemia. 44 WARNINGS 45 THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM 46 ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL 47 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND 48 BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS. 49 ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY 50 UNDER MEDICAL SUPERVISION. CHANGES IN PURITY, STRENGTH, 51 BRAND (MANUFACTURER), TYPE (REGULAR, NPH, LENTE®, ETC), 52 SPECIES (BEEF, PORK, BEEF-PORK, HUMAN), AND/OR METHOD OF 53 MANUFACTURE (rDNA VERSUS ANIMAL-SOURCE INSULIN) MAY 54 RESULT IN THE NEED FOR A CHANGE IN DOSAGE. 55 SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN, 56 LILLY) MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH 57 ANIMAL-SOURCE INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY 58 OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS 59 OR MONTHS. 60 This insulin preparation contains 500 units of insulin in each milliliter. Extreme caution 61 must be observed in the measurement of dosage because inadvertent overdose may result 62 in irreversible insulin shock. Serious consequences may result if it is used other than under 63 constant medical supervision. 64 PRECAUTIONS 65 General — Every patient exhibiting insulin resistance who requires Humulin R (U-500) for 66 control of diabetes should be under close observation until appropriate dosage is established. The 67 response will vary among patients. Some patients can be controlled with a single dose daily; 68 others may require 2 or 3 injections per day. Most patients will show a “tolerance” to insulin, so 69 that minor variations in dosage can occur without the development of untoward symptoms of 70 insulin shock. 71 Insulin resistance is frequently self-limited; after several weeks or months during which high 72 dosage is required, responsiveness to the pharmacologic effect of insulin may be regained and 73 dosage can be reduced. 74 Information for Patients — Patients should be instructed regarding their dosage and should be 75 reminded that this formulation requires the administration of a smaller volume of solution than is 76 the case with less concentrated formulations. 77 Laboratory Tests — Blood and urine glucose, glycohemoglobin, and urine ketones should be 78 monitored frequently. 79 Drug Interactions — The concurrent use of oral hypoglycemic agents with Humulin R (U-500) 80 is not recommended since there are no data to support such use. 81 Pregnancy-Teratogenic Effects — No reproduction studies have been conducted in animals, 82 and there are no adequate and well-controlled studies in pregnant women. It would be 83 anticipated that the benefits of this insulin preparation would outweigh any risk to the 84 developing fetus. 85 Nonteratogenic Effects — Insulin does not cross the placenta as does glucose. 86 Labor and Delivery — Careful monitoring of the patient is required, since the insulin 87 requirement may decrease following delivery. 88 Nursing Mothers — It is not known whether insulin is excreted in significant amounts in 89 human milk. Because many drugs are excreted in human milk, caution should be exercised when 90 Humulin R (U-500) insulin injection is administered to a nursing woman. 91 Pediatric Use — There are no special precautions relating to the use of this insulin formulation 92 in the pediatric age group. 93 ADVERSE REACTIONS 94 As with other human insulin preparations, hypoglycemic reactions may be associated with the 95 administration of Humulin R (U-500). However, deep secondary hypoglycemic reactions may 96 develop 18 to 24 hours after the original injection of Humulin R (U-500). Consequently, patients 97 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 should be carefully observed, and prompt treatment of such reactions should be initiated with 98 glucagon injections and/or with glucose by intravenous injection or gavage. 99 Hypoglycemia 100 Hypoglycemia is one of the most frequent adverse events experienced by insulin users. 101 Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: 102 • sweating • drowsiness 103 • dizziness • sleep disturbances 104 • palpitation • anxiety 105 • tremor • blurred vision 106 • hunger • slurred speech 107 • restlessness • depressive mood 108 • tingling in the hands, feet, lips, or tongue • irritability 109 • lightheadedness • abnormal behavior 110 • inability to concentrate • unsteady movement 111 • headache • personality changes 112 Signs of severe hypoglycemia can include: 113 • disorientation • seizures 114 • unconsciousness • death 115 Early warning symptoms of hypoglycemia may be different or less pronounced under certain 116 conditions, such as long duration of diabetes, diabetic nerve disease, medications such as 117 beta-blockers, change in insulin preparations, or intensified control (3 or more insulin injections 118 per day) of diabetes. 119 A few patients who have experienced hypoglycemic reactions after transfer from 120 animal-source insulin to human insulin have reported that the early warning symptoms of 121 hypoglycemia were less pronounced or different from those experienced with their 122 previous insulin. 123 Without recognition of early warning symptoms, the patient may not be able to take steps to 124 avoid more serious hypoglycemia. Patients who experience hypoglycemia without early warning 125 symptoms should monitor their blood glucose frequently, especially prior to activities such as 126 driving. Mild to moderate hypoglycemia may be treated by eating foods or taking drinks that 127 contain sugar. Patients should always carry a quick source of sugar, such as candy mints or 128 glucose tablets. 129 Hypoglycemia when using Humulin R (U-500) can be prolonged and severe. 130 Lipodystrophy 131 Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the 132 skin) or lipohypertrophy (enlargement or thickening of tissue). 133 Allergy to Insulin 134 Local Allergy — Patients occasionally experience erythema, local edema, and pruritus at the 135 site of injection of insulin. This condition usually is self-limiting. In some instances, this 136 condition may be related to factors other than insulin, such as irritants in the skin cleansing agent 137 or poor injection technique. 138 Systemic Allergy — Less common, but potentially more serious, is generalized allergy to 139 insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in 140 blood pressure, fast pulse, or sweating. Severe cases of generalized allergy (anaphylaxis) may be 141 life threatening. 142 DOSAGE AND ADMINISTRATION 143 Humulin R (U-500) should only be administered subcutaneously. It is inadvisable to inject 144 Humulin R (U-500) intravenously because of possible inadvertent overdosage. 145 It is recommended that an insulin syringe or tuberculin-type syringe be used for the 146 measurement of dosage. Variations in dosage are frequently possible in the insulin-resistant 147 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 patient, since the individual is unresponsive to the pharmacologic effect of the insulin. 148 Nevertheless, accuracy of measurement is to be encouraged because of the potential danger of 149 the preparation. 150 STORAGE 151 Insulin should be kept in a cold place, preferably in a refrigerator, but must not be frozen. 152 Do not inject insulin that is not water-clear. Discoloration, turbidity, or unusual viscosity 153 indicates deterioration or contamination. 154 Use of a package of insulin should not be started after the expiration date stamped on it. 155 HOW SUPPLIED 156 Vials, 500 units/mL, 20 mL (HI-500) (1s), NDC 0002-8501-01 157 158 Literature revised April 9, 2007 159 Eli Lilly and Company, Indianapolis, IN 46285, USA 160 PA 3052 AMP PRINTED IN USA 161 Copyright © 1996, 2007, Eli Lilly and Company. All rights reserved. 162 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 PA 3052 AMP 163 INFORMATION FOR THE PATIENT 164 HUMULIN® R 165 REGULAR 166 U-500 (CONCENTRATED) 167 INSULIN HUMAN INJECTION, USP 168 (rDNA ORIGIN) 169 170 WARNINGS 171 THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM 172 ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL 173 TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND 174 BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS. 175 ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY 176 UNDER MEDICAL SUPERVISION. CHANGES IN PURITY, STRENGTH, 177 BRAND (MANUFACTURER), TYPE (REGULAR, NPH, E.G., LENTE), SPECIES 178 (BEEF, PORK, BEEF-PORK, HUMAN), AND/OR METHOD OF 179 MANUFACTURE (rDNA VERSUS ANIMAL-SOURCE INSULIN) MAY 180 RESULT IN THE NEED FOR A CHANGE IN DOSAGE. 181 SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN, 182 LILLY) MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH 183 ANIMAL-SOURCE INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY 184 OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS 185 OR MONTHS. 186 This insulin preparation contains 500 units of insulin in each milliliter. Extreme caution 187 must be observed in the measurement of dosage because inadvertent overdose may result 188 in irreversible insulin shock. Serious consequences may result if it is used other than under 189 constant medical supervision. 190 DIABETES 191 Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This 192 hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when 193 the pancreas does not make enough insulin to meet your body’s needs. 194 To control your diabetes, your doctor has prescribed injections of insulin products to keep your 195 blood glucose at a near-normal level. You have been instructed to test your blood and/or your 196 urine regularly for glucose. Studies have shown that some chronic complications of diabetes 197 such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood 198 sugar is maintained as close to normal as possible. The American Diabetes Association 199 recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your 200 hemoglobin A1c (HbA1c) is more than 7%, consult your doctor. A change in your diabetes 201 therapy may be needed. If your blood tests consistently show below-normal glucose levels you 202 should also let your doctor know. Proper control of your diabetes requires close and constant 203 cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat 204 a balanced diet, exercise regularly, and take your insulin injections as prescribed. 205 Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always 206 wear diabetic identification so that appropriate treatment can be given if complications occur 207 away from home. 208 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 REGULAR HUMAN INSULIN 209 Description 210 Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia 211 coli bacteria that has been genetically altered by the addition of the gene for human insulin 212 production. Humulin R (U-500) consists of zinc-insulin crystals dissolved in a clear fluid. 213 Humulin R (U-500) has had nothing added to change the speed or length of its action. It takes 214 effect rapidly but has a relatively long duration of activity (up to 24 hours) as compared with 215 other Regular insulins. The time course of action of any insulin may vary considerably in 216 different individuals or at different times in the same individual. As with all insulin preparations, 217 the duration of action of Humulin R (U-500) is dependent on dose, site of injection, blood 218 supply, temperature, and physical activity. Humulin R (U-500), is a sterile solution and is for 219 subcutaneous injection only. It should not be used intravenously or intramuscularly. The 220 concentration of Humulin R (U-500) is 500 units/mL. 221 Identification 222 Human insulin by Eli Lilly and Company has the trademark Humulin and is available in 223 6 formulations — Regular (R), NPH (N), Lente (L), Ultralente® (U), 50% Human Insulin 224 Isophane Suspension [NPH]/50% Human Insulin Injection [regular] (50/50), and 70% Human 225 Insulin Isophane Suspension [NPH]/30% Human Insulin Injection [regular] (70/30). Humulin R 226 (U-500) is the only human insulin by Eli Lilly and Company that has a concentration of 227 500 units/mL. Your doctor has prescribed the type of insulin that he/she believes is best for you. 228 DO NOT USE ANY OTHER INSULIN EXCEPT ON HIS/HER ADVICE AND 229 DIRECTION. 230 Always check the carton and the bottle label for the name and letter designation of the insulin 231 you receive from your pharmacy to make sure it is the same as that your doctor has prescribed. 232 Always examine the appearance of your bottle of insulin before withdrawing each dose. 233 Humulin R (U-500) is a clear and colorless liquid with a water-like appearance and consistency. 234 Do not use if it appears cloudy, thickened, or slightly colored or if solid particles are visible. 235 Always check the appearance of your bottle of insulin before using, and if you note anything 236 unusual in the appearance of your insulin or notice your insulin requirements changing 237 markedly, consult your doctor. 238 Storage 239 Insulin should be stored in a refrigerator but not in the freezer. If refrigeration is not possible, 240 the bottle of insulin that you are currently using can be kept unrefrigerated as long as it is kept as 241 cool as possible (below 30°C [86°F]) and away from heat and light. Do not use insulin if it has 242 been frozen. Do not use a bottle of Humulin R (U-500) after the expiration date stamped on the 243 label. 244 INJECTION PROCEDURES 245 Correct Syringe Type 246 Doses of insulin are measured in units. U-500 insulin contains 500 units/mL (1 mL=1 cc). 247 With Humulin R (U-500), it is important to use a tuberculin (or similar) syringe as instructed by 248 your doctor. Failure to use the proper syringe type can lead to a mistake in dosage, causing 249 serious problems for you, such as a blood glucose level that is too low or too high. 250 Syringe Use 251 To help avoid contamination and possible infection, follow these instructions exactly. 252 Disposable plastic syringes and needles should be used only once and then discarded in a 253 responsible manner. NEEDLES AND SYRINGES MUST NOT BE SHARED. 254 Reusable glass syringes and needles must be sterilized before each injection. Follow the 255 package directions supplied with your syringe. Described below are 2 methods of sterilizing. 256 Boiling 257 1. Put syringe, plunger, and needle in strainer, place in saucepan, and cover with water. Boil 258 for 5 minutes. 259 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 2. Remove articles from water. When they have cooled, insert plunger into barrel, and fasten 260 needle to syringe with a slight twist. 261 3. Push plunger in and out several times until water is completely removed. 262 Isopropyl Alcohol 263 If the syringe, plunger, and needle cannot be boiled, as when you are traveling, they may be 264 sterilized by immersion for at least 5 minutes in Isopropyl Alcohol, 91%. Do not use bathing, 265 rubbing, or medicated alcohol for this sterilization. If the syringe is sterilized with alcohol, it 266 must be absolutely dry before use. 267 Preparing the Dose 268 1. Wash your hands. 269 2. Inspect the insulin. Humulin R (U-500) should look clear and colorless. Do not use 270 Humulin R (U-500) if it appears cloudy, thickened, or slightly colored or if solid particles 271 are visible. 272 3. If using a new bottle, flip off the plastic protective cap, but do not remove the stopper. 273 When using a new bottle, wipe the top of the bottle with an alcohol swab. 274 4. Draw air into the syringe equal to your insulin dose. Put the needle through the rubber top 275 of the insulin bottle and inject the air into the bottle. 276 5. Turn the bottle and syringe upside down. Hold the bottle and syringe firmly in one hand. 277 6. Making sure the tip of the needle is in the insulin, withdraw the correct dose of insulin 278 into the syringe. 279 7. Before removing the needle from the bottle, check your syringe for air bubbles which 280 reduce the amount of insulin in it. If bubbles are present, hold the syringe straight up and 281 tap its side until the bubbles float to the top. Push them out with the plunger and withdraw 282 the correct dose. 283 8. Remove the needle from the bottle and lay the syringe down so that the needle does not 284 touch anything. 285 Injection 286 Once you have chosen an injection site, cleanse the skin with alcohol where the injection is to 287 be made. Stabilize the skin by spreading it or pinching up a large area. Insert the needle as 288 instructed by your doctor. Push the plunger in as far as it will go. Pull the needle out and apply 289 gentle pressure over the injection site for several seconds. Do not rub the area. To avoid tissue 290 damage, give the next injection at a site at least 1/2 inch from the previous site. 291 DOSAGE 292 Your doctor has told you which insulin to use, how much, and when and how often to inject it. 293 Because each patient’s case of diabetes is different, this schedule has been individualized for 294 you. 295 Your usual insulin dose may be affected by changes in your food, activity, or work schedule. 296 Carefully follow your doctor’s instructions to allow for these changes. Other things that may 297 affect your insulin dose are: 298 Illness 299 Illness, especially with nausea and vomiting, may cause your insulin requirements to change. 300 Even if you are not eating, you will still require insulin. You and your doctor should establish a 301 sick day plan for you to use in case of illness. When you are sick, test your blood glucose/urine 302 glucose and ketones frequently and call your doctor as instructed. 303 Pregnancy 304 Good control of diabetes is especially important for you and your unborn baby. Pregnancy may 305 make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or 306 are nursing a baby, consult your doctor. 307 Medication 308 Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising 309 activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin 310 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 requirements may be reduced in the presence of drugs with blood-glucose-lowering activity, 311 such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, 312 certain antidepressants and some kidney and blood pressure medicines. Your Health Care 313 Professional may be aware of other medications that may affect your diabetes control. Therefore, 314 always discuss any medications you are taking with your doctor. 315 Exercise 316 Exercise may lower your body’s need for insulin during and for some time after the activity. 317 Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the 318 area of injection site (for example, the leg should not be used for injection just prior to running). 319 Discuss with your doctor how you should adjust your regimen to accommodate exercise. 320 Travel 321 Persons traveling across more than 2 time zones should consult their doctor concerning 322 adjustments in their insulin schedule. 323 COMMON PROBLEMS OF DIABETES 324 Hypoglycemia (Low Blood Sugar) 325 Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events 326 experienced by insulin users. It can be brought about by: 327 1. Missing or delaying meals. 328 2. Taking too much insulin. 329 3. Exercising or working more than usual. 330 4. An infection or illness (especially with diarrhea or vomiting). 331 5. A change in the body’s need for insulin. 332 6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver 333 disease. 334 7. Interactions with other drugs that lower blood glucose, such as oral antidiabetic agents, 335 salicylates (for example, aspirin), sulfa antibiotics, certain antidepressants and some 336 kidney and blood pressure medicines. 337 8. Consumption of alcoholic beverages. 338 Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: 339 • sweating • drowsiness 340 • dizziness • sleep disturbances 341 • palpitation • anxiety 342 • tremor • blurred vision 343 • hunger • slurred speech 344 • restlessness • depressive mood 345 • tingling in the hands, feet, lips, or tongue • irritability 346 • lightheadedness • abnormal behavior 347 • inability to concentrate • unsteady movement 348 • headache • personality changes 349 Signs of severe hypoglycemia can include: 350 • disorientation • seizures 351 • unconsciousness • death 352 Therefore, it is important that assistance be obtained immediately. 353 Early warning symptoms of hypoglycemia may be different or less pronounced under certain 354 conditions, such as long duration of diabetes, diabetic nerve disease, medications such as 355 beta-blockers, change in insulin preparations, or intensified control (3 or more insulin injections 356 per day) of diabetes. 357 A few patients who have experienced hypoglycemic reactions after transfer from 358 animal-source insulin to human insulin have reported that the early warning symptoms of 359 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 hypoglycemia were less pronounced or different from those experienced with their 360 previous insulin. 361 Without recognition of early warning symptoms, you may not be able to take steps to avoid 362 more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate 363 hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should 364 monitor their blood glucose frequently, especially prior to activities such as driving. If the blood 365 glucose is below your normal fasting glucose, you should consider eating or drinking 366 sugar-containing foods to treat your hypoglycemia. 367 Mild to moderate hypoglycemia may be treated by eating foods or taking drinks that contain 368 sugar. Patients should always carry a quick source of sugar, such as candy mints or glucose 369 tablets. More severe hypoglycemia may require the assistance of another person. Patients who 370 are unable to take sugar orally or who are unconscious require an injection of glucagon or should 371 be treated with intravenous administration of glucose at a medical facility. 372 Hypoglycemia when using Humulin R (U-500) can be prolonged and severe. All 373 hypoglycemic episodes should be reported to your doctor. 374 You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain 375 about these symptoms, you should monitor your blood glucose frequently to help you learn to 376 recognize the symptoms that you experience with hypoglycemia. 377 If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the 378 symptoms, you should consult your doctor to discuss possible changes in therapy, meal plans, 379 and/or exercise programs to help you avoid hypoglycemia. 380 Hyperglycemia and Diabetic Ketoacidosis (DKA) 381 Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin. 382 Hyperglycemia can be brought about by: 383 1. Omitting your insulin or taking less than the doctor has prescribed. 384 2. Eating significantly more than your meal plan suggests. 385 3. Developing a fever, infection, or other significant stressful situation. 386 In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in 387 DKA. The first symptoms of DKA usually come on gradually, over a period of hours or days, 388 and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on the breath. 389 With DKA, urine tests show large amounts of glucose and ketones. Heavy breathing and a rapid 390 pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia or DKA can lead to 391 nausea, vomiting, dehydration, loss of consciousness or death. Therefore, it is important that you 392 obtain medical assistance immediately. 393 Lipodystrophy 394 Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the 395 skin) or lipohypertrophy (enlargement or thickening of tissue). If you notice either of these 396 conditions, consult your doctor. A change in your injection technique may help alleviate the 397 problem. 398 Allergy to Insulin 399 Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of 400 injection of insulin. This condition, called local allergy, usually clears up in a few days to a few 401 weeks. In some instances, this condition may be related to factors other than insulin, such as 402 irritants in the skin cleansing agent or poor injection technique. If you have local reactions, 403 contact your doctor. 404 Systemic Allergy — Less common, but potentially more serious, is generalized allergy to 405 insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in 406 blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life 407 threatening. If you think you are having a generalized allergic reaction to insulin, notify a doctor 408 immediately. 409 ADDITIONAL INFORMATION 410 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Additional information about diabetes may be obtained from your diabetes educator. 411 DIABETES FORECAST is a magazine designed especially for people with diabetes and their 412 families. It is available by subscription from the American Diabetes Association (ADA), P.O. 413 Box 363, Mt. Morris, IL 61054-0363, 1-800-DIABETES (1-800-342-2383). 414 Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research 415 Foundation International (JDRFI), 120 Wall Street 19th Floor, New York, NY 10005, 416 1-800-533-CURE (1-800-533-2873). 417 Additional information about Humulin can be obtained by calling The Lilly Answers Center at 418 1-800-LillyRx (1-800-545-5979). 419 420 Patient Information revised April 9, 2007 421 Eli Lilly and Company, Indianapolis, IN 46285, USA 422 PA 3052 AMP PRINTED IN USA 423 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:57.520702	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018780s114lbl.pdf', 'application_number': 18780, 'submission_type': 'SUPPL ', 'submission_number': 114}
11,325	1 A1.0 NL 5691 AMP A1.0 NL 5681 AMP A2.0 NL 4460 AMP INFORMATION FOR THE PATIENT 10 mL Vial (1000 Units per vial) HUMULIN® R REGULAR INSULIN HUMAN INJECTION, USP (rDNA ORIGIN) 100 UNITS PER ML (U-100) WARNINGS THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS. ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE. SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS. DIABETES Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when the pancreas does not make enough insulin to meet your body’s needs. To control your diabetes, your doctor has prescribed injections of insulin products to keep your blood glucose at a near-normal level. You have been instructed to test your blood and/or your urine regularly for glucose. Studies have shown that some chronic complications of diabetes such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar is maintained as close to normal as possible. The American Diabetes Association recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may be needed. If your blood tests consistently show below-normal glucose levels, you should also let your doctor know. Proper control of your diabetes requires close and constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by your doctor. Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always wear diabetic identification so that appropriate treatment can be given if complications occur away from home. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 REGULAR HUMAN INSULIN Description Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered to produce human insulin. Humulin R [Regular insulin human injection, USP (rDNA origin)] consists of zinc-insulin crystals dissolved in a clear fluid. Humulin R has had nothing added to change the speed or length of its action. It takes effect rapidly and has a relatively short duration of activity (4 to 12 hours) as compared with other insulins. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. As with all insulin preparations, the duration of action of Humulin R is dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin R is a sterile solution and is for subcutaneous injection. It should not be used intramuscularly. The concentration of Humulin R is 100 units/mL (U-100). Identification Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND DIRECTION. Always check the carton and the bottle label for the name and letter designation of the insulin you receive from your pharmacy to make sure it is the same as prescribed by your doctor. Always check the appearance of your bottle of Humulin R before withdrawing each dose. Humulin R is a clear and colorless liquid with a water-like appearance and consistency. Do not use Humulin R: • if it appears cloudy, thickened, or slightly colored, or • if solid particles are visible. If you see anything unusual in the appearance of Humulin R solution in your bottle or notice your insulin requirements changing, talk to your doctor. Storage Not in-use (unopened): Humulin R bottles not in-use should be stored in a refrigerator, but not in the freezer. In-use (opened): The Humulin R bottle you are currently using can be kept unrefrigerated as long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light. Do not use Humulin R after the expiration date stamped on the label or if it has been frozen. INSTRUCTIONS FOR INSULIN VIAL USE NEVER SHARE NEEDLES AND SYRINGES. Correct Syringe Type Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc). With Humulin R, it is important to use a syringe that is marked for U-100 insulin preparations. Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for you, such as a blood glucose level that is too low or too high. Syringe Use To help avoid contamination and possible infection, follow these instructions exactly. Disposable syringes and needles should be used only once and then discarded by placing the used needle in a puncture-resistant disposable container. Properly dispose of the puncture- resistant container as directed by your Health Care Professional. Preparing the Dose 1. Wash your hands. 2. Inspect the insulin. Humulin R solution should look clear and colorless. Do not use Humulin R if it appears cloudy, thickened, or slightly colored, or if you see particles in the solution. Do not use Humulin R if you notice anything unusual in its appearance. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 3. If using a new Humulin R bottle, flip off the plastic protective cap, but do not remove the stopper. Wipe the top of the bottle with an alcohol swab. 4. If you are mixing insulins, refer to the “Mixing Humulin R with Longer-Acting Human Insulins” section below. 5. Draw an amount of air into the syringe that is equal to the Humulin R dose. Put the needle through rubber top of the Humulin R bottle and inject the air into the bottle. 6. Turn the Humulin R bottle and syringe upside down. Hold the bottle and syringe firmly in one hand. 7. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose of Humulin R into the syringe. 8. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles. If bubbles are present, hold the syringe straight up and tap its side until the bubbles float to the top. Push the bubbles out with the plunger and then withdraw the correct dose. 9. Remove the needle from the bottle and lay the syringe down so that the needle does not touch anything. 10. If you do not need to mix your Humulin R with a longer-acting insulin, go to the “Injection Instructions” section below and follow the directions. Mixing Humulin R with Longer-Acting Human Insulins 1. Humulin R should be mixed with longer-acting human insulins only on the advice of your doctor. 2. Draw an amount of air into the syringe that is equal to the amount of longer-acting insulin you are taking. Insert the needle into the longer-acting insulin bottle and inject the air. Withdraw the needle. 3. Draw an amount of air into the syringe that is equal to the amount of Humulin R you are taking. Insert the needle into the Humulin R bottle and inject the air, but do not withdraw the needle. 4. Turn the Humulin R bottle and syringe upside down. 5. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose of Humulin R into the syringe. 6. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles. If bubbles are present, hold the syringe straight up and tap its side until the bubbles float to the top. Push the bubbles out with the plunger and then withdraw the correct dose. 7. Remove the syringe with the needle from the Humulin R bottle and insert it into the longer-acting insulin bottle. Turn the longer-acting insulin bottle and syringe upside down. Hold the bottle and syringe firmly in one hand and shake gently. Making sure the tip of the needle is in the longer-acting insulin, withdraw the correct dose of longer-acting insulin. 8. Remove the needle from the bottle and lay the syringe down so that the needle does not touch anything. 9. Follow the directions under “Injection Instructions” section below. Follow your doctor’s instructions on whether to mix your insulins ahead of time or just before giving your injection. It is important to be consistent in your method. Syringes from different manufacturers may vary in the amount of space between the bottom line and the needle. Because of this, do not change: • the sequence of mixing, or • the model and brand of syringe or needle that your doctor has prescribed. Injection Instructions 1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the previous injection site. The usual sites of injection are abdomen, thighs, and arms. 2. Cleanse the skin with alcohol where the injection is to be made. 3. With one hand, stabilize the skin by spreading it or pinching up a large area. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 4. Insert the needle as instructed by your doctor. 5. Push the plunger in as far as it will go. 6. Pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area. 7. Place the used needle in a puncture-resistant disposable container and properly dispose of the puncture-resistant container as directed by your Health Care Professional. DOSAGE Your doctor has told you which insulin to use, how much, and when and how often to inject it. Because each patient’s diabetes is different, this schedule has been individualized for you. Your usual dose of Humulin R may be affected by changes in your diet, activity, or work schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things that may affect your Humulin R dose are: Illness Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you will still require insulin. You and your doctor should establish a sick day plan for you to use in case of illness. When you are sick, test your blood glucose frequently. If instructed by your doctor, test your ketones and report the results to your doctor. Pregnancy Good control of diabetes is especially important for you and your unborn baby. Pregnancy may make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or are nursing a baby, talk to your doctor. Medication Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin requirements may be reduced in the presence of drugs that lower blood glucose or affect how your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines. Your Health Care Professional may be aware of other medications that may affect your diabetes control. Therefore, always discuss any medications you are taking with your doctor. Exercise Exercise may lower your body’s need for insulin during and for some time after the physical activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the area of injection site (for example, the leg should not be used for injection just prior to running). Discuss with your doctor how you should adjust your insulin regimen to accommodate exercise. Travel When traveling across more than 2 time zones, you should talk to your doctor concerning adjustments in your insulin schedule. COMMON PROBLEMS OF DIABETES Hypoglycemia (Low Blood Sugar) Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events experienced by insulin users. It can be brought about by: 1. Missing or delaying meals. 2. Taking too much insulin. 3. Exercising or working more than usual. 4. An infection or illness associated with diarrhea or vomiting. 5. A change in the body’s need for insulin. 6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver disease. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure medicines. 8. Consumption of alcoholic beverages. Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: • sweating • drowsiness • dizziness • sleep disturbances • palpitation • anxiety • tremor • blurred vision • hunger • slurred speech • restlessness • depressed mood • tingling in the hands, feet, lips, or tongue • irritability • lightheadedness • abnormal behavior • inability to concentrate • unsteady movement • headache • personality changes Signs of severe hypoglycemia can include: • disorientation • seizures • unconsciousness • death Therefore, it is important that assistance be obtained immediately. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes. A few patients who have experienced hypoglycemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin. Without recognition of early warning symptoms, you may not be able to take steps to avoid more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose frequently, especially prior to activities such as driving. If the blood glucose is below your normal fasting glucose, you should consider eating or drinking sugar-containing foods to treat your hypoglycemia. Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar. Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More severe hypoglycemia may require the assistance of another person. Patients who are unable to take sugar orally or who are unconscious require an injection of glucagon or should be treated with intravenous administration of glucose at a medical facility. You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain about these symptoms, you should monitor your blood glucose frequently to help you learn to recognize the symptoms that you experience with hypoglycemia. If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans, and/or exercise programs to help you avoid hypoglycemia. Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA) Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin. Hyperglycemia can be brought about by any of the following: 1. Omitting your insulin or taking less than your doctor has prescribed. 2. Eating significantly more than your meal plan suggests. 3. Developing a fever, infection, or other significant stressful situation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually, over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss of consciousness, or death. Therefore, it is important that you obtain medical assistance immediately. Lipodystrophy Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either of these conditions, talk to your doctor. A change in your injection technique may help alleviate the problem. Allergy Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor. Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life threatening. If you think you are having a generalized allergic reaction to insulin, call your doctor immediately. ADDITIONAL INFORMATION Information about diabetes may be obtained from your diabetes educator. Additional information about diabetes and Humulin can be obtained by calling The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com. Patient Information issued/revised Month dd, yyyy Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Hospira, Inc., Lake Forest, IL 60045, USA or Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA A1.0 NL 5691 AMP PRINTED IN USA A1.0 NL5681 AMP A2.0 NL 4460 AMP Copyright © 1997, yyyy, Eli Lilly and Company. All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 A1.0 NL 5711 AMP A1.0 NL 6792 AMP INFORMATION FOR THE PATIENT 10 mL Vial (1000 Units per vial) HUMULIN® N NPH HUMAN INSULIN (rDNA ORIGIN) ISOPHANE SUSPENSION 100 UNITS PER ML (U-100) WARNINGS THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS. ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE. SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS. DIABETES Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when the pancreas does not make enough insulin to meet your body’s needs. To control your diabetes, your doctor has prescribed injections of insulin products to keep your blood glucose at a near-normal level. You have been instructed to test your blood and/or your urine regularly for glucose. Studies have shown that some chronic complications of diabetes such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar is maintained as close to normal as possible. The American Diabetes Association recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may be needed. If your blood tests consistently show below-normal glucose levels, you should also let your doctor know. Proper control of your diabetes requires close and constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by your doctor. Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always wear diabetic identification so that appropriate treatment can be given if complications occur away from home. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 NPH HUMAN INSULIN Description Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered to produce human insulin. Humulin N [Human insulin (rDNA origin) isophane suspension] is a crystalline suspension of human insulin with protamine and zinc providing an intermediate-acting insulin with a slower onset of action and a longer duration of activity (up to 24 hours) than that of Regular human insulin. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. As with all insulin preparations, the duration of action of Humulin N is dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin N is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously or intramuscularly. The concentration of Humulin N is 100 units/mL (U-100). Identification Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND DIRECTION. Always check the carton and the bottle label for the name and letter designation of the insulin you receive from your pharmacy to make sure it is the same as prescribed by your doctor. Always check the appearance of your bottle of Humulin N before withdrawing each dose. Before each injection the Humulin N bottle must be carefully shaken or rotated several times to completely mix the insulin. Humulin N suspension should look uniformly cloudy or milky after mixing. If not, repeat the above steps until contents are mixed. Do not use Humulin N: • if the insulin substance (the white material) remains at the bottom of the bottle after mixing or • if there are clumps in the insulin after mixing, or • if solid white particles stick to the bottom or wall of the bottle, giving a frosted appearance. If you see anything unusual in the appearance of Humulin N suspension in your bottle or notice your insulin requirements changing, talk to your doctor. Storage Not in-use (unopened): Humulin N bottles not in-use should be stored in a refrigerator, but not in the freezer. In-use (opened): The Humulin N bottle you are currently using can be kept unrefrigerated as long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light. Do not use Humulin N after the expiration date stamped on the label or if it has been frozen. INSTRUCTIONS FOR INSULIN VIAL USE NEVER SHARE NEEDLES AND SYRINGES. Correct Syringe Type Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc). With Humulin N, it is important to use a syringe that is marked for U-100 insulin preparations. Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for you, such as a blood glucose level that is too low or too high. Syringe Use To help avoid contamination and possible infection, follow these instructions exactly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Disposable syringes and needles should be used only once and then discarded by placing the used needle in a puncture-resistant disposable container. Properly dispose of the puncture- resistant container as directed by your Health Care Professional. Preparing the Dose 1. Wash your hands. 2. Carefully shake or rotate the bottle of insulin several times to completely mix the insulin. 3. Inspect the insulin. Humulin N suspension should look uniformly cloudy or milky. Do not use Humulin N if you notice anything unusual in its appearance. 4. If using a new Humulin N bottle, flip off the plastic protective cap, but do not remove the stopper. Wipe the top of the bottle with an alcohol swab. 5. If you are mixing insulins, refer to the “Mixing Humulin N and Regular Human Insulin” section below. 6. Draw an amount of air into the syringe that is equal to the Humulin N dose. Put the needle through rubber top of the Humulin N bottle and inject the air into the bottle. 7. Turn the Humulin N bottle and syringe upside down. Hold the bottle and syringe firmly in one hand and shake gently. 8. Making sure the tip of the needle is in the Humulin N suspension, withdraw the correct dose of Humulin N into the syringe. 9. Before removing the needle from the Humulin N bottle, check the syringe for air bubbles. If bubbles are present, hold the syringe straight up and tap its side until the bubbles float to the top. Push the bubbles out with the plunger and then withdraw the correct dose. 10. Remove the needle from the bottle and lay the syringe down so that the needle does not touch anything. 11. If you do not need to mix your Humulin N with Regular human insulin, go to the “Injection Instructions” section below and follow the directions. Mixing Humulin N and Regular Human Insulin (Humulin R) 1. Humulin N should be mixed with Humulin R only on the advice of your doctor. 2. Draw an amount of air into the syringe that is equal to the amount of Humulin N you are taking. Insert the needle into the Humulin N bottle and inject the air. Withdraw the needle. 3. Draw an amount of air into the syringe that is equal to the amount of Humulin R you are taking. Insert the needle into the Humulin R bottle and inject the air, but do not withdraw the needle. 4. Turn the Humulin R bottle and syringe upside down. 5. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose of Humulin R into the syringe. 6. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles. If bubbles are present, hold the syringe straight up and tap its side until the bubbles float to the top. Push the bubbles out with the plunger and then withdraw the correct dose. 7. Remove the syringe with the needle from the Humulin R bottle and insert it into the Humulin N bottle. Turn the Humulin R bottle and syringe upside down. Hold the bottle and syringe firmly in one hand and shake gently. Making sure the tip of the needle is in the Humulin N, withdraw the correct dose of Humulin N. 8. Remove the needle from the bottle and lay the syringe down so that the needle does not touch anything. 9. Follow the directions under “Injection Instructions” section below. Follow your doctor’s instructions on whether to mix your insulins ahead of time or just before giving your injection. It is important to be consistent in your method. Syringes from different manufacturers may vary in the amount of space between the bottom line and the needle. Because of this, do not change: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 • the sequence of mixing, or • the model and brand of syringe or needle that your doctor has prescribed. Injection Instructions 1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the previous injection site. The usual sites of injection are abdomen, thighs, and arms. 2. Cleanse the skin with alcohol where the injection is to be made. 3. With one hand, stabilize the skin by spreading it or pinching up a large area. 4. Insert the needle as instructed by your doctor. 5. Push the plunger in as far as it will go. 6. Pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area. 7. Place the used needle in a puncture-resistant disposable container and properly dispose of the puncture-resistant container as directed by your Health Care Professional. DOSAGE Your doctor has told you which insulin to use, how much, and when and how often to inject it. Because each patient’s diabetes is different, this schedule has been individualized for you. Your usual dose of Humulin N may be affected by changes in your diet, activity, or work schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things that may affect your Humulin N dose are: Illness Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you will still require insulin. You and your doctor should establish a sick day plan for you to use in case of illness. When you are sick, test your blood glucose frequently. If instructed by your doctor, test your ketones and report the results to your doctor. Pregnancy Good control of diabetes is especially important for you and your unborn baby. Pregnancy may make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or are nursing a baby, talk to your doctor. Medication Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin requirements may be reduced in the presence of drugs that lower blood glucose or affect how your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines. Your Health Care Professional may be aware of other medications that may affect your diabetes control. Therefore, always discuss any medications you are taking with your doctor. Exercise Exercise may lower your body’s need for insulin during and for some time after the physical activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the area of injection site (for example, the leg should not be used for injection just prior to running). Discuss with your doctor how you should adjust your insulin regimen to accommodate exercise. Travel When traveling across more than 2 time zones, you should talk to your doctor concerning adjustments in your insulin schedule. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 COMMON PROBLEMS OF DIABETES Hypoglycemia (Low Blood Sugar) Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events experienced by insulin users. It can be brought about by: 1. Missing or delaying meals. 2. Taking too much insulin. 3. Exercising or working more than usual. 4. An infection or illness associated with diarrhea or vomiting. 5. A change in the body’s need for insulin. 6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver disease. 7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure medicines. 8. Consumption of alcoholic beverages. Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: • sweating • drowsiness • dizziness • sleep disturbances • palpitation • anxiety • tremor • blurred vision • hunger • slurred speech • restlessness • depressed mood • tingling in the hands, feet, lips, or tongue • irritability • lightheadedness • abnormal behavior • inability to concentrate • unsteady movement • headache • personality changes Signs of severe hypoglycemia can include: • disorientation • seizures • unconsciousness • death Therefore, it is important that assistance be obtained immediately. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes. A few patients who have experienced hypoglycemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin. Without recognition of early warning symptoms, you may not be able to take steps to avoid more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose frequently, especially prior to activities such as driving. If the blood glucose is below your normal fasting glucose, you should consider eating or drinking sugar-containing foods to treat your hypoglycemia. Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar. Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More severe hypoglycemia may require the assistance of another person. Patients who are unable to take sugar orally or who are unconscious require an injection of glucagon or should be treated with intravenous administration of glucose at a medical facility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain about these symptoms, you should monitor your blood glucose frequently to help you learn to recognize the symptoms that you experience with hypoglycemia. If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans, and/or exercise programs to help you avoid hypoglycemia. Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA) Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin. Hyperglycemia can be brought about by any of the following: 1. Omitting your insulin or taking less than your doctor has prescribed. 2. Eating significantly more than your meal plan suggests. 3. Developing a fever, infection, or other significant stressful situation. In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually, over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss of consciousness, or death. Therefore, it is important that you obtain medical assistance immediately. Lipodystrophy Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either of these conditions, talk to your doctor. A change in your injection technique may help alleviate the problem. Allergy Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor. Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life threatening. If you think you are having a generalized allergic reaction to insulin, call your doctor immediately. ADDITIONAL INFORMATION Information about diabetes may be obtained from your diabetes educator. Additional information about diabetes and Humulin can be obtained by calling The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com. Patient Information issued/revised Month dd, yyyy Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA A1.0 NL 5711 AMP A1.0 NL 6792 AMP PRINTED IN USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Copyright © 1997, yyyy, Eli Lilly and Company. All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 A1.0 NL 3682 AMP 1 2 3 4 5 6 7 8 9 A6.0 PA 9134 FSAMP INFORMATION FOR THE PATIENT 3 ML DISPOSABLE INSULIN DELIVERY DEVICE HUMULIN® N Pen NPH HUMAN INSULIN (rDNA ORIGIN) ISOPHANE SUSPENSION 100 UNITS PER ML (U-100) WARNINGS 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL- SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN PRODUCED BY YOUR BODY'S PANCREAS AND BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS. ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE. SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS. TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW THE INSULIN DELIVERY DEVICE USER MANUAL AND THIS “INFORMATION FOR THE PATIENT” INSERT BEFORE USING THIS PRODUCT. BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A NECESSARY STEP TO MAKE SURE THE PEN IS READY TO DOSE. PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES OUT WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR THAT MAY COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE TOO MUCH OR TOO LITTLE INSULIN (see also INSTRUCTIONS FOR INSULIN PEN USE section). DIABETES Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This hormone is necessary for the body's correct use of food, especially sugar. Diabetes occurs when the pancreas does not make enough insulin to meet your body's needs. To control your diabetes, your doctor has prescribed injections of insulin products to keep your blood glucose at a near-normal level. You have been instructed to test your blood and/or your urine regularly for glucose. Studies have shown that some chronic complications of diabetes such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar is maintained as close to normal as possible. The American Diabetes Association recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may be needed. If your blood tests consistently show below-normal glucose This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 levels, you should also let your doctor know. Proper control of your diabetes requires close and constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by your doctor. Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always wear diabetic identification so that appropriate treatment can be given if complications occur away from home. NPH HUMAN INSULIN Description Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered to produce human insulin. Humulin N [Human insulin (rDNA origin) isophane suspension] is a crystalline suspension of human insulin with protamine and zinc providing an intermediate-acting insulin with a slower onset of action and a longer duration of activity (up to 24 hours) than that of Regular human insulin. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. As with all insulin preparations, the duration of action of Humulin N is dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin N is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously or intramuscularly. The concentration of Humulin N is 100 units/mL (U-100). Identification Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND DIRECTION. The Humulin N Pen is available in boxes of 5 disposable insulin delivery devices (“insulin Pens”). The Humulin N Pen is not designed to allow any other insulin to be mixed in its cartridge, or for the cartridge to be removed. Always check the carton and the Pen label for the name and letter designation of the insulin you receive from your pharmacy to make sure it is the same as prescribed by your doctor. Always check the appearance of Humulin N suspension in your insulin Pen before using. A cartridge of Humulin N contains a small glass bead to assist in mixing. Roll the Pen between the palms 10 times (see Figure 1). Holding the Pen by one end, invert it 180° slowly 10 times to allow the small glass bead to travel the full length with each inversion (see Figure 2). Figure 1. Figure 2. Humulin N suspension should look uniformly cloudy or milky after mixing. If not, repeat the above steps until contents are mixed. Pens containing Humulin N suspension should be examined frequently. Do not use Humulin N: • if the insulin substance (the white material) remains visibly separated from the liquid after mixing or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 • if there are clumps in the insulin after mixing, or 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 • if solid white particles stick to the walls of the cartridge, giving a frosted appearance. If you see anything unusual in the appearance of the Humulin N suspension in your Pen or notice your insulin requirements changing, talk to your doctor. Never attempt to remove the cartridge from the Humulin N Pen. Inspect the cartridge through the clear cartridge holder. Storage Not in-use (unopened): Humulin N Pens not in-use should be stored in a refrigerator, but not in the freezer. In-use (opened): Humulin N Pens in-use should NOT be refrigerated but should be kept at room temperature [below 86°F (30°C)] away from direct heat and light. The Humulin N Pen you are currently using must be discarded 2 weeks after the first use, even if it still contains Humulin N. Do not use Humulin N after the expiration date stamped on the label or if it has been frozen. INSTRUCTIONS FOR INSULIN PEN USE It is important to read, understand, and follow the instructions in the Insulin Delivery Device User Manual before using. Failure to follow instructions may result in getting too much or too little insulin. The needle must be changed and the Pen must be primed before each injection to make sure the Pen is ready to dose. Performing these steps before each injection is important to confirm that insulin comes out when you push the injection button, and to remove air that may collect in the insulin cartridge during normal use. Every time you inject: • Use a new needle. • Prime to make sure the Pen is ready to dose. • Make sure you got your full dose. NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES. PREPARING FOR INJECTION 1. Wash your hands. 2. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the previous injection site. The usual sites of injection are abdomen, thighs, and arms. 3. Follow the instructions in your Insulin Delivery Device User Manual to prepare for injection. 4. After injecting the dose, pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area. 5. After the injection, remove the needle from the Humulin N Pen. Do not reuse needles. 6. Place the used needle in a puncture-resistant disposable container and properly dispose of the puncture-resistant container as directed by your Health Care Professional. DOSAGE Your doctor has told you which insulin to use, how much, and when and how often to inject it. Because each patient's diabetes is different, this schedule has been individualized for you. Your usual dose of Humulin N may be affected by changes in your diet, activity, or work schedule. Carefully follow your doctor's instructions to allow for these changes. Other things that may affect your Humulin N dose are: Illness Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you will still require insulin. You and your doctor should establish a sick day plan for you to use in case of illness. When you are sick, test your blood glucose frequently. If instructed by your doctor, test your ketones and report the results to your doctor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Pregnancy 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 Good control of diabetes is especially important for you and your unborn baby. Pregnancy may make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or are nursing a baby, talk to your doctor. Medication Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin requirements may be reduced in the presence of drugs that lower blood glucose or affect how your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines. Your Health Care Professional may be aware of other medications that may affect your diabetes control. Therefore, always discuss any medications you are taking with your doctor. Exercise Exercise may lower your body's need for insulin during and for some time after the physical activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the area of injection site (for example, the leg should not be used for injection just prior to running). Discuss with your doctor how you should adjust your insulin regimen to accommodate exercise. Travel When traveling across more than 2 time zones, you should talk to your doctor concerning adjustments in your insulin schedule. COMMON PROBLEMS OF DIABETES Hypoglycemia (Low Blood Sugar) Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events experienced by insulin users. It can be brought about by: 1. Missing or delaying meals. 2. Taking too much insulin. 3. Exercising or working more than usual. 4. An infection or illness associated with diarrhea or vomiting. 5. A change in the body's need for insulin. 6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver disease. 7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure medicines. 8. Consumption of alcoholic beverages. Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: • sweating • drowsiness • dizziness • sleep disturbances • palpitation • anxiety • tremor • blurred vision • hunger • slurred speech • restlessness • depressed mood • tingling in the hands, feet, lips, or tongue • irritability • lightheadedness • abnormal behavior • inability to concentrate • unsteady movement • headache • personality changes Signs of severe hypoglycemia can include: • disorientation • seizures • unconsciousness • death This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Therefore, it is important that assistance be obtained immediately. 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes. A few patients who have experienced hypoglycemic reactions after transfer from animal- source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin. Without recognition of early warning symptoms, you may not be able to take steps to avoid more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose frequently, especially prior to activities such as driving. If the blood glucose is below your normal fasting glucose, you should consider eating or drinking sugar- containing foods to treat your hypoglycemia. Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar. Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More severe hypoglycemia may require the assistance of another person. Patients who are unable to take sugar orally or who are unconscious require an injection of glucagon or should be treated with intravenous administration of glucose at a medical facility. You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain about these symptoms, you should monitor your blood glucose frequently to help you learn to recognize the symptoms that you experience with hypoglycemia. If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans, and/or exercise programs to help you avoid hypoglycemia. Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA) Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin. Hyperglycemia can be brought about by any of the following: 1. Omitting your insulin or taking less than your doctor has prescribed. 2. Eating significantly more than your meal plan suggests. 3. Developing a fever, infection, or other significant stressful situation. In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually, over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss of consciousness, or death. Therefore, it is important that you obtain medical assistance immediately. Lipodystrophy Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either of these conditions, talk to your doctor. A change in your injection technique may help alleviate the problem. Allergy Local Allergy ⎯ Patients occasionally experience redness, swelling, and itching at the site of injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Systemic Allergy ⎯ Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life threatening. If you think you are having a generalized allergic reaction to insulin, call your doctor immediately. 237 238 239 240 241 242 243 244 245 246 ADDITIONAL INFORMATION Information about diabetes may be obtained from your diabetes educator. Additional information about diabetes and Humulin can be obtained by calling The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com. Patient Information issued/revised Month dd, yyyy Pens manufactured by 247 248 249 250 251 252 253 254 255 Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA A1.0 NL 3682 AMP PRINTED IN USA A6.0 PA 9134 FSAMP Copyright © 1998, yyyy, Eli Lilly and Company. All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 A1.0 NL 5721 AMP A3.0 NL 3770 AMP INFORMATION FOR THE PATIENT 10 mL Vial (1000 Units per vial) HUMULIN® 70/30 70% HUMAN INSULIN ISOPHANE SUSPENSION AND 30% HUMAN INSULIN INJECTION (rDNA ORIGIN) 100 UNITS PER ML (U-100) WARNINGS THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS. ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE. SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS. DIABETES Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when the pancreas does not make enough insulin to meet your body’s needs. To control your diabetes, your doctor has prescribed injections of insulin products to keep your blood glucose at a near-normal level. You have been instructed to test your blood and/or your urine regularly for glucose. Studies have shown that some chronic complications of diabetes such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar is maintained as close to normal as possible. The American Diabetes Association recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may be needed. If your blood tests consistently show below-normal glucose levels, you should also let your doctor know. Proper control of your diabetes requires close and constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by your doctor. Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always wear diabetic identification so that appropriate treatment can be given if complications occur away from home. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 70/30 HUMAN INSULIN Description Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered to produce human insulin. Humulin 70/30 is a mixture of 70% Human Insulin Isophane Suspension and 30% Human Insulin Injection (rDNA origin). It is an intermediate-acting insulin combined with the more rapid onset of action of Regular human insulin. The duration of activity may last up to 24 hours following injection. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. As with all insulin preparations, the duration of action of Humulin 70/30 is dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin 70/30 is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously or intramuscularly. The concentration of Humulin 70/30 is 100 units/mL (U-100). Identification Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND DIRECTION. Always check the carton and the bottle label for the name and letter designation of the insulin you receive from your pharmacy to make sure it is the same as prescribed by your doctor. Always check the appearance of your bottle of Humulin 70/30 before withdrawing each dose. Before each injection the Humulin 70/30 bottle must be carefully shaken or rotated several times to completely mix the insulin. Humulin 70/30 suspension should look uniformly cloudy or milky after mixing. If not, repeat the above steps until contents are mixed. Do not use Humulin 70/30: • if the insulin substance (the white material) remains at the bottom of the bottle after mixing or • if there are clumps in the insulin after mixing, or • if solid white particles stick to the bottom or wall of the bottle, giving a frosted appearance. If you see anything unusual in the appearance of Humulin 70/30 suspension in your bottle or notice your insulin requirements changing, talk to your doctor. Storage Not in-use (unopened): Humulin 70/30 bottles not in-use should be stored in a refrigerator, but not in the freezer. In-use (opened): The Humulin 70/30 bottle you are currently using can be kept unrefrigerated as long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light. Do not use Humulin 70/30 after the expiration date stamped on the label or if it has been frozen. INSTRUCTIONS FOR INSULIN VIAL USE NEVER SHARE NEEDLES AND SYRINGES Correct Syringe Type Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc). With Humulin 70/30, it is important to use a syringe that is marked for U-100 insulin preparations. Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for you, such as a blood glucose level that is too low or too high. Syringe Use To help avoid contamination and possible infection, follow these instructions exactly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Disposable syringes and needles should be used only once and then discarded by placing the used needle in a puncture-resistant disposable container. Properly dispose of the puncture- resistant container as directed by your Health Care Professional. Preparing the Dose 1. Wash your hands. 2. Carefully shake or rotate the bottle of insulin several times to completely mix the insulin. 3. Inspect the insulin. Humulin 70/30 suspension should look uniformly cloudy or milky. Do not use Humulin 70/30 if you notice anything unusual in its appearance. 4. If using a new Humulin 70/30 bottle, flip off the plastic protective cap, but do not remove the stopper. Wipe the top of the bottle with an alcohol swab. 5. Draw an amount of air into the syringe that is equal to the Humulin 70/30 dose. Put the needle through rubber top of the Humulin 70/30 bottle and inject the air into the bottle. 6. Turn the Humulin 70/30 bottle and syringe upside down. Hold the bottle and syringe firmly in one hand and shake gently. 7. Making sure the tip of the needle is in the Humulin 70/30 suspension, withdraw the correct dose of Humulin 70/30 into the syringe. 8. Before removing the needle from the Humulin 70/30 bottle, check the syringe for air bubbles. If bubbles are present, hold the syringe straight up and tap its side until the bubbles float to the top. Push the bubbles out with the plunger and then withdraw the correct dose. 9. Remove the needle from the bottle and lay the syringe down so that the needle does not touch anything. Injection Instructions 1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the previous injection site. The usual sites of injection are abdomen, thighs, and arms. 2. Cleanse the skin with alcohol where the injection is to be made. 3. With one hand, stabilize the skin by spreading it or pinching up a large area. 4. Insert the needle as instructed by your doctor. 5. Push the plunger in as far as it will go. 6. Pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area. 7. Place the used needle in a puncture-resistant disposable container and properly dispose of the puncture-resistant container as directed by your Health Care Professional. DOSAGE Your doctor has told you which insulin to use, how much, and when and how often to inject it. Because each patient’s diabetes is different, this schedule has been individualized for you. Your usual dose of Humulin 70/30 may be affected by changes in your diet, activity, or work schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things that may affect your Humulin 70/30 dose are: Illness Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you will still require insulin. You and your doctor should establish a sick day plan for you to use in case of illness. When you are sick, test your blood glucose frequently. If instructed by your doctor, test your ketones and report the results to your doctor. Pregnancy Good control of diabetes is especially important for you and your unborn baby. Pregnancy may make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or are nursing a baby, talk to your doctor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Medication Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin requirements may be reduced in the presence of drugs that lower blood glucose or affect how your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines. Your Health Care Professional may be aware of other medications that may affect your diabetes control. Therefore, always discuss any medications you are taking with your doctor. Exercise Exercise may lower your body’s need for insulin during and for some time after the physical activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the area of injection site (for example, the leg should not be used for injection just prior to running). Discuss with your doctor how you should adjust your insulin regimen to accommodate exercise. Travel When traveling across more than 2 time zones, you should talk to your doctor concerning adjustments in your insulin schedule. COMMON PROBLEMS OF DIABETES Hypoglycemia (Low Blood Sugar) Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events experienced by insulin users. It can be brought about by: 1. Missing or delaying meals. 2. Taking too much insulin. 3. Exercising or working more than usual. 4. An infection or illness associated with diarrhea or vomiting. 5. A change in the body’s need for insulin. 6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver disease. 7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure medicines. 8. Consumption of alcoholic beverages. Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: • sweating • drowsiness • dizziness • sleep disturbances • palpitation • anxiety • tremor • blurred vision • hunger • slurred speech • restlessness • depressed mood • tingling in the hands, feet, lips, or tongue • irritability • lightheadedness • abnormal behavior • inability to concentrate • unsteady movement • headache • personality changes Signs of severe hypoglycemia can include: • disorientation • seizures • unconsciousness • death Therefore, it is important that assistance be obtained immediately. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes. A few patients who have experienced hypoglycemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin. Without recognition of early warning symptoms, you may not be able to take steps to avoid more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose frequently, especially prior to activities such as driving. If the blood glucose is below your normal fasting glucose, you should consider eating or drinking sugar-containing foods to treat your hypoglycemia. Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar. Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More severe hypoglycemia may require the assistance of another person. Patients who are unable to take sugar orally or who are unconscious require an injection of glucagon or should be treated with intravenous administration of glucose at a medical facility. You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain about these symptoms, you should monitor your blood glucose frequently to help you learn to recognize the symptoms that you experience with hypoglycemia. If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans, and/or exercise programs to help you avoid hypoglycemia. Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA) Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin. Hyperglycemia can be brought about by any of the following: 1. Omitting your insulin or taking less than your doctor has prescribed. 2. Eating significantly more than your meal plan suggests. 3. Developing a fever, infection, or other significant stressful situation. In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually, over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss of consciousness, or death. Therefore, it is important that you obtain medical assistance immediately. Lipodystrophy Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either of these conditions, talk to your doctor. A change in your injection technique may help alleviate the problem. Allergy Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life threatening. If you think you are having a generalized allergic reaction to insulin, call your doctor immediately. ADDITIONAL INFORMATION Information about diabetes may be obtained from your diabetes educator. Additional information about diabetes and Humulin can be obtained by calling The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com. Patient Information issued/revised Month dd, yyyy Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA A1.0 NL 5721 AMP PRINTED IN USA A3.0 NL 3770 AMP Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 A1.0 NL 3672 AMP A2.0 PA 9145 FSAMP INFORMATION FOR THE PATIENT 3 ML DISPOSABLE INSULIN DELIVERY DEVICE HUMULIN® 70/30 Pen 70% HUMAN INSULIN ISOPHANE SUSPENSION AND 30% HUMAN INSULIN INJECTION (rDNA ORIGIN) 100 UNITS PER ML (U-100) WARNINGS THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS. ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE. SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS. TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW THE INSULIN DELIVERY DEVICE USER MANUAL AND THIS “INFORMATION FOR THE PATIENT” INSERT BEFORE USING THIS PRODUCT. BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A NECESSARY STEP TO MAKE SURE THE PEN IS READY TO DOSE. PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES OUT WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR THAT MAY COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE TOO MUCH OR TOO LITTLE INSULIN (see also INSTRUCTIONS FOR INSULIN PEN USE section). DIABETES Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when the pancreas does not make enough insulin to meet your body’s needs. To control your diabetes, your doctor has prescribed injections of insulin products to keep your blood glucose at a near-normal level. You have been instructed to test your blood and/or your urine regularly for glucose. Studies have shown that some chronic complications of diabetes such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar is maintained as close to normal as possible. The American Diabetes Association This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may be needed. If your blood tests consistently show below-normal glucose levels, you should also let your doctor know. Proper control of your diabetes requires close and constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by your doctor. Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always wear diabetic identification so that appropriate treatment can be given if complications occur away from home. 70/30 HUMAN INSULIN Description Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered to produce human insulin. Humulin 70/30 is a mixture of 70% Human Insulin Isophane Suspension and 30% Human Insulin Injection, (rDNA origin). It is an intermediate-acting insulin combined with the more rapid onset of action of Regular human insulin. The duration of activity may last up to 24 hours following injection. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. As with all insulin preparations, the duration of action of Humulin 70/30 is dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin 70/30 is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously or intramuscularly. The concentration of Humulin 70/30 is 100 units/mL (U-100). Identification Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND DIRECTION. The Humulin 70/30 Pen is available in boxes of 5 disposable insulin delivery devices (“insulin Pens”). The Humulin 70/30 Pen is not designed to allow any other insulin to be mixed in its cartridge, or for the cartridge to be removed. Always check the carton and the Pen label for the name and letter designation of the insulin you receive from your pharmacy to make sure it is the same as prescribed by your doctor. Always check the appearance of Humulin 70/30 suspension in your insulin Pen before using. A cartridge of Humulin 70/30 contains a small glass bead to assist in mixing. Roll the Pen between the palms 10 times (see Figure 1). Holding the Pen by one end, invert it 180° slowly 10 times to allow the small glass bead to travel the full length with each inversion (see Figure 2). Figure 1. Figure 2. Humulin 70/30 suspension should look uniformly cloudy or milky after mixing. If not, repeat the above steps until contents are mixed. Pens containing Humulin 70/30 suspension should be examined frequently. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Do not use Humulin 70/30: • if the insulin substance (the white material) remains visibly separated from the liquid after mixing or • if there are clumps in the insulin after mixing, or • if solid white particles stick to the walls of the cartridge, giving a frosted appearance. If you see anything unusual in the appearance of the Humulin 70/30 suspension in your Pen or notice your insulin requirements changing, talk to your doctor. Never attempt to remove the cartridge from the Humulin 70/30 Pen. Inspect the cartridge through the clear cartridge holder. Storage Not in-use (unopened): Humulin 70/30 Pens not in-use should be stored in a refrigerator, but not in the freezer. In-use (opened): Humulin 70/30 Pens in-use should NOT be refrigerated but should be kept at room temperature [below 86ºF (30ºC)] away from direct heat and light. The Humulin 70/30 Pen you are currently using must be discarded 10 days after the first use, even if it still contains Humulin 70/30. Do not use Humulin 70/30 after the expiration date stamped on the label or if it has been frozen. INSTRUCTIONS FOR INSULIN PEN USE It is important to read, understand, and follow the instructions in the Insulin Delivery Device User Manual before using. Failure to follow instructions may result in getting too much or too little insulin. The needle must be changed and the Pen must be primed before each injection to make sure the Pen is ready to dose. Performing these steps before each injection is important to confirm that insulin comes out when you push the injection button, and to remove air that may collect in the insulin cartridge during normal use. Every time you inject: • Use a new needle. • Prime to make sure the Pen is ready to dose. • Make sure you got your full dose. NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES. PREPARING FOR INJECTION 1. Wash your hands. 2. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the previous injection site. The usual sites of injection are abdomen, thighs, and arms. 3. Follow the instructions in your Insulin Delivery Device User Manual to prepare for injection. 4. After injecting the dose, pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area. 5. After the injection, remove the needle from the Humulin 70/30 Pen. Do not reuse needles. 6. Place the used needle in a puncture-resistant disposable container and properly dispose of the puncture-resistant container as directed by your Health Care Professional. DOSAGE Your doctor has told you which insulin to use, how much, and when and how often to inject it. Because each patient’s diabetes is different, this schedule has been individualized for you. Your usual dose of Humulin 70/30 may be affected by changes in your diet, activity, or work schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things that may affect your Humulin 70/30 dose are: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Illness Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you will still require insulin. You and your doctor should establish a sick day plan for you to use in case of illness. When you are sick, test your blood glucose frequently. If instructed by your doctor, test your ketones and report the results to your doctor. Pregnancy Good control of diabetes is especially important for you and your unborn baby. Pregnancy may make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or are nursing a baby, talk to your doctor. Medication Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin requirements may be reduced in the presence of drugs that lower blood glucose or affect how your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines. Your Health Care Professional may be aware of other medications that may affect your diabetes control. Therefore, always discuss any medications you are taking with your doctor. Exercise Exercise may lower your body’s need for insulin during and for some time after the physical activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the area of injection site (for example, the leg should not be used for injection just prior to running). Discuss with your doctor how you should adjust your insulin regimen to accommodate exercise. Travel When traveling across more than 2 time zones, you should talk to your doctor concerning adjustments in your insulin schedule. COMMON PROBLEMS OF DIABETES Hypoglycemia (Low Blood Sugar) Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events experienced by insulin users. It can be brought about by: 1. Missing or delaying meals. 2. Taking too much insulin. 3. Exercising or working more than usual. 4. An infection or illness associated with diarrhea or vomiting. 5. A change in the body’s need for insulin. 6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver disease. 7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure medicines. 8. Consumption of alcoholic beverages. Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: • sweating • drowsiness • dizziness • sleep disturbances • palpitation • anxiety • tremor • blurred vision • hunger • slurred speech • restlessness • depressed mood • tingling in the hands, feet, lips, or tongue • irritability • lightheadedness • abnormal behavior This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 • inability to concentrate • unsteady movement • headache • personality changes Signs of severe hypoglycemia can include: • disorientation • seizures • unconsciousness • death Therefore, it is important that assistance be obtained immediately. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes. A few patients who have experienced hypoglycemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin. Without recognition of early warning symptoms, you may not be able to take steps to avoid more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose frequently, especially prior to activities such as driving. If the blood glucose is below your normal fasting glucose, you should consider eating or drinking sugar-containing foods to treat your hypoglycemia. Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar. Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More severe hypoglycemia may require the assistance of another person. Patients who are unable to take sugar orally or who are unconscious require an injection of glucagon or should be treated with intravenous administration of glucose at a medical facility. You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain about these symptoms, you should monitor your blood glucose frequently to help you learn to recognize the symptoms that you experience with hypoglycemia. If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans, and/or exercise programs to help you avoid hypoglycemia. Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA) Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin. Hyperglycemia can be brought about by any of the following: 1. Omitting your insulin or taking less than your doctor has prescribed. 2. Eating significantly more than your meal plan suggests. 3. Developing a fever, infection, or other significant stressful situation. In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually, over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss of consciousness, or death. Therefore, it is important that you obtain medical assistance immediately. Lipodystrophy Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either of these conditions, talk to your doctor. A change in your injection technique may help alleviate the problem. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Allergy Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor. Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life threatening. If you think you are having a generalized allergic reaction to insulin, call your doctor immediately. ADDITIONAL INFORMATION Information about diabetes may be obtained from your diabetes educator. Additional information about diabetes and Humulin can be obtained by calling The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com. Patient Information issued/revised Month dd, yyyy Pens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA A1.0 NL 3672 AMP PRINTED IN USA A2.0 PA 9145 FSAMP Copyright © 1998, yyyy, Eli Lilly and Company. All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 A1.0 NL 5701 AMP 1 A3.0 NL 4590 AMP 2 INFORMATION FOR THE PATIENT 3 10 mL Vial (1000 Units per vial) 4 HUMULIN® 50/50 5 50% HUMAN INSULIN 6 ISOPHANE SUSPENSION 7 AND 8 50% HUMAN INSULIN INJECTION 9 (rDNA ORIGIN) 10 100 UNITS PER ML (U-100) 11 12 WARNINGS 13 THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL- 14 SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE 15 INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS 16 UNIQUE MANUFACTURING PROCESS. 17 ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY 18 UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, 19 MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR 20 METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A 21 CHANGE IN DOSAGE. 22 SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) 23 MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER 24 INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE 25 FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS. 26 DIABETES 27 Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This 28 hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when 29 the pancreas does not make enough insulin to meet your body’s needs. 30 To control your diabetes, your doctor has prescribed injections of insulin products to keep your 31 blood glucose at a near-normal level. You have been instructed to test your blood and/or your 32 urine regularly for glucose. Studies have shown that some chronic complications of diabetes 33 such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood 34 sugar is maintained as close to normal as possible. The American Diabetes Association 35 recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your 36 hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your 37 diabetes therapy may be needed. If your blood tests consistently show below-normal glucose 38 levels, you should also let your doctor know. Proper control of your diabetes requires close and 39 constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life 40 if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by 41 your doctor. 42 Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always 43 wear diabetic identification so that appropriate treatment can be given if complications occur 44 away from home. 45 46 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 50/50 HUMAN INSULIN 47 Description 48 Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia 49 coli bacteria that has been genetically altered to produce human insulin. Humulin 50/50 is a 50 mixture of 50% Human Insulin Isophane Suspension and 50% Human Insulin Injection (rDNA 51 origin). It is an intermediate-acting insulin combined with the more rapid onset of action of 52 Regular human insulin. The duration of activity may last up to 24 hours following injection. The 53 time course of action of any insulin may vary considerably in different individuals or at different 54 times in the same individual. As with all insulin preparations, the duration of action of 55 Humulin 50/50 is dependent on dose, site of injection, blood supply, temperature, and physical 56 activity. Humulin 50/50 is a sterile suspension and is for subcutaneous injection only. It should 57 not be used intravenously or intramuscularly. The concentration of Humulin 50/50 is 58 100 units/mL (U-100). 59 Identification 60 Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has 61 prescribed the type of insulin that he/she believes is best for you. 62 DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND 63 DIRECTION. 64 Always check the carton and the bottle label for the name and letter designation of the insulin 65 you receive from your pharmacy to make sure it is the same as prescribed by your doctor. 66 Always check the appearance of your bottle of Humulin 50/50 before withdrawing each dose. 67 Before each injection the Humulin 50/50 bottle must be carefully shaken or rotated several times 68 to completely mix the insulin. Humulin 50/50 suspension should look uniformly cloudy or milky 69 after mixing. If not, repeat the above steps until contents are mixed. 70 Do not use Humulin 50/50: 71 • if the insulin substance (the white material) remains at the bottom of the bottle after 72 mixing or 73 • if there are clumps in the insulin after mixing, or 74 • if solid white particles stick to the bottom or wall of the bottle, giving a frosted 75 appearance. 76 If you see anything unusual in the appearance of Humulin 50/50 suspension in your bottle or 77 notice your insulin requirements changing, talk to your doctor. 78 Storage 79 Not in-use (unopened): Humulin 50/50 bottles not in-use should be stored in a refrigerator, 80 but not in the freezer. 81 In-use (opened): The Humulin 50/50 bottle you are currently using can be kept unrefrigerated 82 as long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light. 83 Do not use Humulin 50/50 after the expiration date stamped on the label or if it has been 84 frozen. 85 INSTRUCTIONS FOR INSULIN VIAL USE 86 NEVER SHARE NEEDLES AND SYRINGES. 87 Correct Syringe Type 88 Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc). 89 With Humulin 50/50, it is important to use a syringe that is marked for U-100 insulin 90 preparations. Failure to use the proper syringe can lead to a mistake in dosage, causing serious 91 problems for you, such as a blood glucose level that is too low or too high. 92 Syringe Use 93 To help avoid contamination and possible infection, follow these instructions exactly. 94 Disposable syringes and needles should be used only once and then discarded by placing the 95 used needle in a puncture-resistant disposable container. Properly dispose of the puncture- 96 resistant container as directed by your Health Care Professional. 97 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Preparing the Dose 98 1. Wash your hands. 99 2. Carefully shake or rotate the bottle of insulin several times to completely mix the insulin. 100 3. Inspect the insulin. Humulin 50/50 suspension should look uniformly cloudy or milky. Do 101 not use Humulin 50/50 if you notice anything unusual in its appearance. 102 4. If using a new Humulin 50/50 bottle, flip off the plastic protective cap, but do not remove 103 the stopper. Wipe the top of the bottle with an alcohol swab. 104 5. Draw an amount of air into the syringe that is equal to the Humulin 50/50 dose. Put the 105 needle through rubber top of the Humulin 50/50 bottle and inject the air into the bottle. 106 6. Turn the Humulin 50/50 bottle and syringe upside down. Hold the bottle and syringe 107 firmly in one hand and shake gently. 108 7. Making sure the tip of the needle is in the Humulin 50/50 suspension, withdraw the 109 correct dose of Humulin 50/50 into the syringe. 110 8. Before removing the needle from the Humulin 50/50 bottle, check the syringe for air 111 bubbles. If bubbles are present, hold the syringe straight up and tap its side until the 112 bubbles float to the top. Push the bubbles out with the plunger and then withdraw the 113 correct dose. 114 9. Remove the needle from the bottle and lay the syringe down so that the needle does not 115 touch anything. 116 Injection Instructions 117 1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the 118 previous injection site. The usual sites of injection are abdomen, thighs, and arms. 119 2. Cleanse the skin with alcohol where the injection is to be made. 120 3. With one hand, stabilize the skin by spreading it or pinching up a large area. 121 4. Insert the needle as instructed by your doctor. 122 5. Push the plunger in as far as it will go. 123 6. Pull the needle out and apply gentle pressure over the injection site for several seconds. 124 Do not rub the area. 125 7. Place the used needle in a puncture-resistant disposable container and properly dispose of 126 the puncture-resistant container as directed by your Health Care Professional. 127 DOSAGE 128 Your doctor has told you which insulin to use, how much, and when and how often to inject it. 129 Because each patient’s diabetes is different, this schedule has been individualized for you. Your 130 usual dose of Humulin 50/50 may be affected by changes in your diet, activity, or work schedule. 131 Carefully follow your doctor’s instructions to allow for these changes. Other things that may 132 affect your Humulin 50/50 dose are: 133 Illness 134 Illness, especially with nausea and vomiting, may cause your insulin requirements to change. 135 Even if you are not eating, you will still require insulin. You and your doctor should establish a 136 sick day plan for you to use in case of illness. When you are sick, test your blood glucose 137 frequently. If instructed by your doctor, test your ketones and report the results to your doctor. 138 Pregnancy 139 Good control of diabetes is especially important for you and your unborn baby. Pregnancy may 140 make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or 141 are nursing a baby, talk to your doctor. 142 Medication 143 Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising 144 activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin 145 requirements may be reduced in the presence of drugs that lower blood glucose or affect how 146 your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Your Healthcare Professional may be aware of other medications that may affect your diabetes control. Therefore, always discuss any medications you are taking with your doctor. Exercise 151 Exercise may lower your body’s need for insulin during and for some time after the physical 152 activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise 153 involves the area of injection site (for example, the leg should not be used for injection just prior 154 to running). Discuss with your doctor how you should adjust your insulin regimen to 155 accommodate exercise. 156 Travel 157 When traveling across more than 2 time zones, you should talk to your doctor concerning 158 adjustments in your insulin schedule. 159 COMMON PROBLEMS OF DIABETES 160 Hypoglycemia (Low Blood Sugar) 161 Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events 162 experienced by insulin users. It can be brought about by: 163 1. Missing or delaying meals. 164 2. Taking too much insulin. 165 3. Exercising or working more than usual. 166 4. An infection or illness associated with diarrhea or vomiting. 167 5. A change in the body’s need for insulin. 168 6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver 169 disease. 170 7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, certain antidepressants and some 2 kidney and blood pressure medicines. 173 8. Consumption of alcoholic beverages. 174 Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: 175 • sweating • drowsiness 176 • dizziness • sleep disturbances 177 • palpitation • anxiety 178 • tremor • blurred vision 179 • hunger • slurred speech 180 • restlessness • depressed mood 181 • tingling in the hands, feet, lips, or tongue • irritability 182 • lightheadedness • abnormal behavior 183 • inability to concentrate • unsteady movement 184 • headache • personality changes 185 Signs of severe hypoglycemia can include: 186 • disorientation • seizures 187 • unconsciousness • death 188 Therefore, it is important that assistance be obtained immediately. 189 Early warning symptoms of hypoglycemia may be different or less pronounced under certain 190 conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as 191 beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections 192 per day) of diabetes. 193 A few patients who have experienced hypoglycemic reactions after transfer from animal- 194 source insulin to human insulin have reported that the early warning symptoms of 195 hypoglycemia were less pronounced or different from those experienced with their 196 previous insulin. 197 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Without recognition of early warning symptoms, you may not be able to take steps to avoid 198 more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate 199 hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should 200 monitor their blood glucose frequently, especially prior to activities such as driving. If the blood 201 glucose is below your normal fasting glucose, you should consider eating or drinking sugar- 202 containing foods to treat your hypoglycemia. 203 Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar. 204 Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More 205 severe hypoglycemia may require the assistance of another person. Patients who are unable to 206 take sugar orally or who are unconscious require an injection of glucagon or should be treated 207 with intravenous administration of glucose at a medical facility. 208 You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain 209 about these symptoms, you should monitor your blood glucose frequently to help you learn to 210 recognize the symptoms that you experience with hypoglycemia. 211 If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the 212 symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans, 213 and/or exercise programs to help you avoid hypoglycemia. 214 Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA) 215 Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin. 216 Hyperglycemia can be brought about by any of the following: 217 1. Omitting your insulin or taking less than your doctor has prescribed. 218 2. Eating significantly more than your meal plan suggests. 219 3. Developing a fever, infection, or other significant stressful situation. 220 In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in 221 DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually, 222 over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, 223 and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose 224 and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected, 225 prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss 226 of consciousness, or death. Therefore, it is important that you obtain medical assistance 227 immediately. 228 Lipodystrophy 229 Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent 230 depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either 231 of these conditions, talk to your doctor. A change in your injection technique may help alleviate 232 the problem. 233 Allergy 234 Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of 235 injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In 236 some instances, this condition may be related to factors other than insulin, such as irritants in the 237 skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor. 238 Systemic Allergy — Less common, but potentially more serious, is generalized allergy to 239 insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in 240 blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life 241 threatening. If you think you are having a generalized allergic reaction to insulin, call your 242 doctor immediately. 243 ADDITIONAL INFORMATION 244 Information about diabetes may be obtained from your diabetes educator. 245 Additional information about diabetes and Humulin can be obtained by calling The Lilly 246 Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com. 247 248 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Patient Information issued/revised Month dd, yyyy 249 Vials manufactured by 250 Eli Lilly and Company, Indianapolis, IN 46285, USA or 251 Lilly France, F-67640 Fegersheim, France 252 253 for Eli Lilly and Company, Indianapolis, IN 46285, USA 254 A1.0 NL 5701 AMP PRINTED IN USA 255 A3.0 NL 4590 AMP 256 257 Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved. 258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:57.562017	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018780s95,018781s89,019717s69,020100s32lbl.pdf', 'application_number': 18780, 'submission_type': 'SUPPL ', 'submission_number': 95}
11,335	1 Submission date: 8/4/04 2.0 PV 3682 AMP 1 INFORMATION FOR THE PATIENT 2 3 ML DISPOSABLE INSULIN DELIVERY DEVICE 3 HUMULIN® N Pen 4 NPH 5 HUMAN INSULIN 6 (rDNA ORIGIN) ISOPHANE SUSPENSION 7 100 UNITS PER ML (U-100) 8 WARNINGS 9 THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL- 10 SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE 11 INSULIN PRODUCED BY YOUR BODY'S PANCREAS AND BECAUSE OF ITS 12 UNIQUE MANUFACTURING PROCESS. 13 ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY 14 UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, 15 MANUFACTURER, TYPE (E.G., REGULAR, NPH, LENTE, ETC), SPECIES 16 (BEEF, PORK, BEEF-PORK, HUMAN), OR METHOD OF MANUFACTURE 17 (rDNA VERSUS ANIMAL-SOURCE INSULIN) MAY RESULT IN THE NEED 18 FOR A CHANGE IN DOSAGE. 19 SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) 20 MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH 21 ANIMAL-SOURCE INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY 22 OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS 23 OR MONTHS. 24 TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW 25 THE “DISPOSABLE INSULIN DELIVERY DEVICE USER MANUAL” AND 26 THIS “INFORMATION FOR THE PATIENT” INSERT BEFORE USING THIS 27 PRODUCT. 28 BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A 29 NECESSARY STEP TO MAKE SURE THE PEN IS READY TO DOSE. 30 PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES 31 OUT WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR 32 THAT MAY COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL 33 USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE TOO MUCH OR TOO 34 LITTLE INSULIN (see also INSTRUCTIONS FOR INSULIN PEN USE section). 35 DIABETES 36 Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This 37 hormone is necessary for the body's correct use of food, especially sugar. Diabetes occurs when 38 the pancreas does not make enough insulin to meet your body's needs. 39 To control your diabetes, your doctor has prescribed injections of insulin products to keep your 40 blood glucose at a near-normal level. You have been instructed to test your blood and/or your 41 urine regularly for glucose. Studies have shown that some chronic complications of diabetes 42 such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood 43 sugar is maintained as close to normal as possible. The American Diabetes Association 44 recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your 45 hemoglobin A1c (HbA1c) is more than 7%, consult your doctor. A change in your diabetes 46 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Submission date: 8/4/04 therapy may be needed. If your blood tests consistently show below-normal glucose levels, you 47 should also let your doctor know. Proper control of your diabetes requires close and constant 48 cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat 49 a balanced diet, exercise regularly, and take your insulin injections as prescribed. 50 Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always 51 wear diabetic identification so that appropriate treatment can be given if complications occur 52 away from home. 53 NPH HUMAN INSULIN 54 Description 55 Humulin is synthesized in a non-disease-producing special laboratory strain of Escherichia 56 coli bacteria that has been genetically altered by the addition of the human gene for insulin 57 production. Humulin® N (human insulin [rDNA origin] isophane suspension) is a crystalline 58 suspension of human insulin with protamine and zinc providing an intermediate-acting insulin 59 with a slower onset of action and a longer duration of activity (up to 24 hours) than that of 60 regular insulin. The time course of action of any insulin may vary considerably in different 61 individuals or at different times in the same individual. As with all insulin preparations, the 62 duration of action of Humulin N is dependent on dose, site of injection, blood supply, 63 temperature, and physical activity. Humulin N is a sterile suspension and is for subcutaneous 64 injection only. It should not be used intravenously or intramuscularly. The concentration of 65 Humulin N in Humulin N Pen is 100 units/mL (U-100). 66 Identification 67 Humulin disposable insulin delivery devices, by Eli Lilly and Company, are available in 68 2 formulations  NPH and 70/30. 69 Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT 70 USE ANY OTHER INSULIN EXCEPT ON HIS/HER ADVICE AND DIRECTION. 71 The Humulin N Pen is available in boxes of 5 disposable insulin delivery devices (“insulin 72 Pens”). The Humulin N Pen is not designed to allow any other insulin to be mixed in its 73 cartridge, or for the cartridge to be removed. 74 Always examine the appearance of Humulin N suspension in the insulin Pen before 75 administering a dose. A cartridge of Humulin N contains a small glass bead to assist in mixing. 76 Humulin N Pen must be rolled between the palms 10 times and inverted 180° 10 times before 77 each injection so that the contents are uniformly mixed (see Figures 1 and 2). Inspect the 78 Humulin N suspension for uniform mixing and repeat the above steps as necessary. 79 80 Figure 1. Figure 2. 81 82 Humulin N should look uniformly cloudy or milky after mixing. Do not use if the insulin 83 substance (the white material) remains visibly separated from the liquid after mixing. Do not use 84 the Humulin N Pen if there are clumps in the insulin after mixing. Do not use the Humulin N Pen 85 if solid white particles stick to the walls of the cartridge, giving it a frosted appearance. 86 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Submission date: 8/4/04 Always check the appearance of the Humulin N suspension in the insulin Pen before using, 87 and if you note anything unusual in the appearance of Humulin N suspension or notice your 88 insulin requirements changing markedly, consult your doctor. 89 Never attempt to remove the cartridge from the Humulin N Pen. Inspect the cartridge through 90 the clear cartridge holder. 91 Storage 92 Not in-use (unopened): Humulin N Pens not in-use should be stored in a refrigerator but not 93 in the freezer. Do not use Humulin N Pen if it has been frozen. 94 In-use: Humulin N Pens in-use should NOT be refrigerated but should be kept at room 95 temperature (below 86°F [30°C]) away from direct heat and light. Humulin N Pens in-use must 96 be discarded after 2 weeks, even if they still contain Humulin N. 97 Do not use Humulin N Pens after the expiration date stamped on the label. 98 INSTRUCTIONS FOR INSULIN PEN USE 99 It is important to read, understand, and follow the instructions in the “Disposable Insulin 100 Delivery Device User Manual” before using. Failure to follow instructions may result in 101 getting too much or too little insulin. The needle must be changed and the Pen must be 102 primed before each injection to make sure the Pen is ready to dose. Performing these steps 103 before each injection is important to confirm that insulin comes out when you push the 104 injection button, and to remove air that may collect in the insulin cartridge during normal 105 use. 106 Every time you inject: 107 • Use a new needle. 108 • Prime to make sure the Pen is ready to dose. 109 • Make sure you got your full dose. 110 NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES. 111 PREPARING THE INSULIN PEN FOR INJECTION 112 1. Always check the appearance of the Humulin N suspension in the insulin Pen before 113 using. 114 2. Roll the Humulin N Pen between the palms 10 times (see Figure 1). 115 3. Holding the Humulin N Pen by one end, invert it 180° slowly 10 times to allow the small 116 glass bead to travel the full length of the cartridge with each inversion (see Figure 2). The 117 cartridge is contained in the clear cartridge holder of the Humulin N Pen. 118 4. Inspect the appearance of the Humulin N suspension to make sure the contents look 119 uniformly cloudy or milky. If not, repeat the above steps until the contents are mixed. Do 120 not use a Humulin N Pen if there are clumps in the insulin or if solid white particles stick 121 to the walls of the cartridge. 122 5. Follow the instructions in the “Disposable Insulin Delivery Device User Manual” for 123 these steps: 124 • Preparing the Pen 125 • Attaching the Needle. Use a new needle for each injection. 126 • Priming the Pen. The Pen must be primed before each injection to make sure the 127 Pen is ready to dose. Performing the priming step is important to confirm that insulin 128 comes out when you push the injection button, and to remove air that may collect in 129 the insulin cartridge during normal use. 130 • Setting a Dose 131 • Injecting a Dose. To make sure you have received your full dose, you must push 132 the injection button all the way down until you see a diamond (♦) or an arrow 133 (→) in the center of the dose window. 134 • Following an Injection 135 PREPARING FOR INJECTION 136 1. Wash your hands. 137 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Submission date: 8/4/04 2. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the 138 previous injection site. The usual sites of injection are abdomen, thighs, and arms. 139 3. Cleanse the skin with alcohol where the injection is to be made. 140 4. With one hand, stabilize the skin by spreading it or pinching up a large area. 141 5. Inject the dose as instructed by your doctor. Hold the needle under the skin for at least 5 142 seconds after injecting. 143 6. After injecting a dose, pull the needle out and apply gentle pressure over the injection site 144 for several seconds. Do not rub the area. 145 7. Immediately after an injection, remove the needle from the Humulin N Pen. Doing so will 146 guard against contamination, leakage, reentry of air, and needle clogs. Do not reuse 147 needles. Place the used needle in a puncture-resistant disposable container and properly 148 dispose of it as directed by your Health Care Professional. 149 DOSAGE 150 Your doctor has told you which insulin to use, how much, and when and how often to inject it. 151 Because each patient's case of diabetes is different, this schedule has been individualized for you. 152 Your usual Humulin N dose may be affected by changes in your food, activity, or work 153 schedule. Carefully follow your doctor's instructions to allow for these changes. Other things that 154 may affect your Humulin N dose are: 155 Illness 156 Illness, especially with nausea and vomiting, may cause your insulin requirements to change. 157 Even if you are not eating, you will still require insulin. You and your doctor should establish a 158 sick day plan for you to use in case of illness. When you are sick, test your blood glucose/urine 159 glucose and ketones frequently and call your doctor as instructed. 160 Pregnancy 161 Good control of diabetes is especially important for you and your unborn baby. Pregnancy may 162 make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or 163 are nursing a baby, consult your doctor. 164 Medication 165 Insulin requirements may be increased if you are taking other drugs with hyperglycemic 166 activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin 167 requirements may be reduced in the presence of drugs with blood-glucose-lowering activity, 168 such as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, and 169 certain antidepressants. Always discuss any medications you are taking with your doctor. 170 Exercise 171 Exercise may lower your body's need for insulin during and for some time after the physical 172 activity. Exercise may also speed up the effect of a Humulin N dose, especially if the exercise 173 involves the area of injection site (for example, the leg should not be used for injection just prior 174 to running). Discuss with your doctor how you should adjust your regimen to accommodate 175 exercise. 176 Travel 177 Persons traveling across more than 2 time zones should consult their doctor concerning 178 adjustments in their insulin schedule. 179 COMMON PROBLEMS OF DIABETES 180 Hypoglycemia (Low Blood Sugar) 181 Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events 182 experienced by insulin users. It can be brought about by: 183 1. Taking too much insulin. 184 2. Missing or delaying meals. 185 3. Exercising or working more than usual. 186 4. An infection or illness (especially with diarrhea or vomiting). 187 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Submission date: 8/4/04 5. A change in the body's need for insulin. 188 6. Diseases of the adrenal, pituitary or thyroid gland, or progression of kidney or liver 189 disease. 190 7. Interactions with other drugs that lower blood glucose, such as oral antidiabetic agents, 191 salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants. 192 8. Consumption of alcoholic beverages. 193 Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: 194 • sweating • drowsiness 195 • dizziness • sleep disturbances 196 • palpitation • anxiety 197 • tremor • blurred vision 198 • hunger • slurred speech 199 • restlessness • depressed mood 200 • tingling in the hands, feet, lips, or tongue • irritability 201 • lightheadedness • abnormal behavior 202 • inability to concentrate • unsteady movement 203 • headache • personality changes 204 Signs of severe hypoglycemia can include: 205 • disorientation • seizures 206 • unconsciousness • death 207 Therefore, it is important that assistance be obtained immediately. 208 Early warning symptoms of hypoglycemia may be different or less pronounced under certain 209 conditions, such as long duration of diabetes, diabetic nerve disease, medications such as beta- 210 blockers, change in insulin preparations, or intensified control (3 or more insulin injections per 211 day) of diabetes. 212 A few patients who have experienced hypoglycemic reactions after transfer from animal- 213 source insulin to human insulin have reported that the early warning symptoms of 214 hypoglycemia were less pronounced or different from those experienced with their 215 previous insulin. 216 Without recognition of early warning symptoms, you may not be able to take steps to avoid 217 more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate 218 hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should 219 monitor their blood glucose frequently, especially prior to activities such as driving. If the blood 220 glucose is below your normal fasting glucose, you should consider eating or drinking sugar- 221 containing foods to treat your hypoglycemia. 222 Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar. 223 Patients should always carry a quick source of sugar, such as candy mints or glucose tablets. 224 More severe hypoglycemia may require the assistance of another person. Patients who are unable 225 to take sugar orally or who are unconscious require an injection of glucagon or should be treated 226 with intravenous administration of glucose at a medical facility. 227 You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain 228 about these symptoms, you should monitor your blood glucose frequently to help you learn to 229 recognize the symptoms that you experience with hypoglycemia. 230 If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the 231 symptoms, you should consult your doctor to discuss possible changes in therapy, meal plans, 232 and/or exercise programs to help you avoid hypoglycemia. 233 Hyperglycemia and Diabetic Ketoacidosis (DKA) 234 Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin. 235 Hyperglycemia can be brought about by: 236 1. Omitting your insulin or taking less than the doctor has prescribed. 237 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Submission date: 8/4/04 2. Eating significantly more than your meal plan suggests. 238 3. Developing a fever, infection, or other significant stressful situation. 239 In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in 240 DKA. The first symptoms of DKA usually come on gradually, over a period of hours or days, 241 and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on the breath. 242 With DKA, urine tests show large amounts of glucose and ketones. Heavy breathing and a rapid 243 pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia or DKA can lead to 244 nausea, vomiting, stomach pains, dehydration, loss of consciousness or death. Therefore, it is 245 important that you obtain medical assistance immediately. 246 Lipodystrophy 247 Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the 248 skin) or lipohypertrophy (enlargement or thickening of tissue). If you notice either of these 249 conditions, consult your doctor. A change in your injection technique may help alleviate the 250 problem. 251 Allergy to Insulin 252 Local Allergy  Patients occasionally experience redness, swelling, and itching at the site of 253 injection of insulin. This condition, called local allergy, usually clears up in a few days to a few 254 weeks. In some instances, this condition may be related to factors other than insulin, such as 255 irritants in the skin cleansing agent or poor injection technique. If you have local reactions, 256 contact your doctor. 257 Systemic Allergy  Less common, but potentially more serious, is generalized allergy to 258 insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in 259 blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life 260 threatening. If you think you are having a generalized allergic reaction to insulin, notify a doctor 261 immediately. 262 ADDITIONAL INFORMATION 263 Additional information about diabetes may be obtained from your diabetes educator. 264 DIABETES FORECAST is a magazine designed especially for people with diabetes and their 265 families. It is available by subscription from the American Diabetes Association, P.O. Box 363, 266 Mt. Morris, IL 61054-0363, 1-800-DIABETES (1-800-342-2383). 267 Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research 268 Foundation International (JDRFI), 120 Wall Street 19th Floor, New York, NY 10005, 269 1-800-533-CURE (1-800-533-2873). 270 Additional information about Humulin and Humulin N Pens can be obtained by calling The 271 Lilly Answers Center at 1-800-LillyRx (1-800-545-5979). 272 Literature revised Month dd, 2004 273 Eli Lilly and Company, Indianapolis, IN 46285, USA 274 2.0 PV 3682 AMP PRINTED IN USA 275 Copyright © 1998, 2004, Eli Lilly and Company. All rights reserved. 276 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Submission date: 8/4/04 3.0 PV 3734 AMP 1 ____________________________________________________________________________ 2 Lilly 3 4 Disposable Insulin Delivery Device 5 User Manual 6 ____________________________________________________________________________ 7 8 Instructions for Use 9 Read and follow all of these instructions carefully. If you do not follow these instructions 10 completely, you may get too much or too little insulin. 11 12 Every time you inject: 13 • Use a new needle 14 • Prime to make sure the Pen is ready to dose 15 • Make sure you got your full dose (see page 18) 16 17 Also, read the “INFORMATION FOR THE PATIENT” 18 insert enclosed in your Pen box. 19 20 Pen Features 21 • A multiple dose, disposable insulin delivery device 22 (“insulin Pen”) containing 3 mL (300 units) of U-100 23 insulin 24 • Delivers up to 60 units per dose 25 • Doses can be dialed by single units 26 27 28 29 30 ___________________________________________________________________________ 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Submission date: 8/4/04 Table of Contents 32 ______________________________________________________________________ 33 34 Pen Parts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 35 36 Important Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 37 38 Preparing the Pen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 39 40 Attaching the Needle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 41 42 Priming the Pen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 43 44 Setting a Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 45 46 Injecting a Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 47 48 Following an Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 49 50 Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 51 ________________________________________________________________________ 52 53 2 54 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Submission date: 8/4/04 Pen Parts 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 3 93 Injection Button Dose Knob Raised Notch Raised Notch Dose Window Label Insulin Cartridge Clear Cartridge Holder Rubber Seal Paper Tab Outer Needle Shield Inner Needle Shield Needle Pen Cap This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Submission date: 8/4/04 94 Important Notes 95 96 • Read and follow all of these instructions carefully. If you do not follow these 97 instructions completely, you may get too much or too little insulin. 98 99 • Use a new needle for each injection. 100 101 • Be sure a needle is completely attached to the Pen before priming, setting the dose 102 and injecting your insulin. 103 104 • Prime every time. 105 106 • The Pen must be primed before each injection to make sure the Pen is ready to dose. 107 Performing the priming step is important to confirm that insulin comes out when you 108 push the injection button, and to remove air that may collect in the insulin cartridge 109 during normal use. See Section III. “Priming the Pen”, pages 10-13. 110 111 • If you do not prime, you may get too much or too little insulin. 112 113 • Make sure you get your full dose. 114 115 • To make sure you get your full dose, you must push the injection button all the way down 116 until you see a diamond (♦) or an arrow (→) in the center of the dose window. See 117 “Following an Injection”, page 18. 118 119 • The numbers on the clear cartridge holder give an estimate of the amount of insulin 120 remaining in the cartridge. Do not use these numbers for measuring an insulin dose. 121 122 • Do not share your Pen. 123 124 125 4 126 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Submission date: 8/4/04 Important Notes 127 (Continued) 128 129 • Keep your Pen out of the reach of children. 130 131 • Pens that have not been used (unopened) should be stored in a refrigerator but not in a 132 freezer. Do not use a Pen if it has been frozen. Refer to the “INFORMATION FOR THE 133 PATIENT” insert for complete storage instructions. 134 135 • After a Pen is used for the first time, it should NOT be refrigerated but should be kept at 136 room temperature [below 86°F (30°C)] and away from direct heat and light. 137 138 • An unrefrigerated Pen should be discarded according to the time specified in the 139 “INFORMATION FOR THE PATIENT” insert, even if it still contains insulin. 140 141 • Never use a Pen after the expiration date stamped on the label. 142 143 • Do not store your Pen with the needle attached. Doing so may allow insulin to leak from the 144 Pen and air bubbles to form in the cartridge. Additionally, with suspension (cloudy) insulins, 145 crystals may clog the needle. 146 147 • Always carry an extra Pen in case yours is lost or damaged. 148 149 • Dispose of empty Pens as instructed by your Health Care Professional and without the needle 150 attached. 151 152 • This Pen is not recommended for use by blind or visually impaired patients without the 153 assistance of a person trained in the proper use of the product. 154 155 • The directions regarding needle handling are not intended to replace local, Health Care 156 Professional, or institutional policies. 157 158 • Any changes in insulin should be made cautiously and only under medical supervision. 159 160 161 5 162 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Submission date: 8/4/04 I. Preparing the Pen 163 164 1. Before proceeding, refer to the “INFORMATION FOR THE PATIENT” insert for instructions on checking the appearance of your insulin. 2. Check the label on the Pen to be sure the Pen contains the type of insulin that has been prescribed for you. 3. Always wash your hands before preparing your Pen for use. 165 4. Pull the Pen cap to remove. 166 6 167 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Submission date: 8/4/04 I. Preparing the Pen 168 (Continued) 169 170 5. If your insulin is a suspension (cloudy): a. Roll the Pen back and forth 10 times then perform step b. 171 b. Gently turn the Pen up and down 10 times until the insulin is evenly mixed. Note: Suspension (cloudy) insulin cartridges contain a small glass bead to assist in mixing. 172 173 6. Use an alcohol swab to wipe the rubber seal on the end of the Pen. 174 7 175 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Submission date: 8/4/04 II. Attaching the Needle 176 177 This device is suitable for use with Becton Dickinson and Company’s insulin pen needles. 178 179 180 1. Always use a new needle for each injection. Do not push injection button without a needle attached. Storing the Pen with the needle attached may allow insulin to leak from the Pen and air bubbles to form in the cartridge. 181 2. Remove the paper tab from the outer needle shield. 182 3. Attach the capped needle onto the end of the Pen by turning it clockwise until tight. 183 8 184 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Submission date: 8/4/04 II. Attaching the Needle 185 (Continued) 186 187 4. Hold the Pen with the needle pointing up and remove the outer needle shield. Keep it to use during needle removal. 188 5. Remove the inner needle shield and discard. 189 190 9 191 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Submission date: 8/4/04 III. Priming the Pen 192 193 • The Pen must be primed before each injection to make sure the Pen is ready to dose. 194 Performing the priming step is important to confirm that insulin comes out when you push the 195 injection button, and to remove air that may collect in the insulin cartridge during normal use. 196 197 • If you do not prime, you may get too much or too little insulin. 198 199 • Always use a new needle for each injection. 200 201 1. Make sure the arrow is in the center of the dose window as shown. 202 2. If you do not see the arrow in the center of the 203 dose window, push in the injection button fully 204 and turn the dose knob until the arrow is seen in 205 the center of the dose window. 206 207 208 Correct 209 210 211 10 212 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Submission date: 8/4/04 III. Priming the Pen 213 (Continued) 214 215 3. With the arrow in the center of the dose window, pull the dose knob out in the direction of the arrow until a “0” is seen in the dose window. 216 4. Turn the dose knob clockwise until the number “2” is seen in the dose window. If the number you have dialed is too high, simply turn the dose knob backward until the number “2” is seen in the dose window. 217 11 218 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Submission date: 8/4/04 219 III. Priming the Pen 220 (Continued) 221 222 5. Hold your Pen with the needle pointing up. Tap the clear cartridge holder gently with your finger so any air bubbles collect near the top. Using your thumb, if possible, push in the injection button completely. Keep pressing and continue to hold the injection button firmly while counting slowly to 5. You should see either a drop or a stream of insulin come out of the tip of the needle. If insulin does not come out of the tip of the needle, repeat steps 1 through 5. If after several attempts insulin does not come out of the tip of the needle, change the needle and repeat the priming steps. 223 224 12 225 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Submission date: 8/4/04 III. Priming the Pen 226 (Continued) 227 228 6. At the completion of the priming step, a diamond (♦) must be seen in the center of the dose window. If a diamond (♦) is not seen in the center of the dose window, continue pushing on the injection button until you see a diamond (♦) in the center of the dose window. 229 230 231 232 233 234 Correct 235 Note: A small air bubble may remain in the cartridge after the completion of the priming step. If you have properly primed the Pen, this small air bubble will not affect your insulin dose. 7. Now you are ready to set your dose. See next page. 236 13 237 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Submission date: 8/4/04 238 IV. Setting a Dose 239 240 • Always use a new needle for each injection. Storing the Pen with the needle attached 241 may allow insulin to leak from the Pen and air bubbles to form in the cartridge. 242 243 • Caution: Do not push in the injection button while setting your dose. Failure to follow 244 these instructions carefully may result in getting too much or too little insulin. If you 245 accidentally push the injection button while setting your dose, you must prime the Pen 246 again before injecting your dose. See Section III. “Priming the Pen”, pages 10-13. 247 248 1. A diamond must be seen in the center of the dose window before setting your dose. If you do not see a diamond in the center of the dose window, the Pen has not been primed correctly and you are not ready to set your dose. Before continuing, repeat the priming steps. Correct 2. Turn the dose knob clockwise until the arrow (→) is seen in the center of the dose window and the notches on the Pen and dose knob are in line. 249 250 14 251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Submission date: 8/4/04 IV. Setting a Dose 252 (Continued) 253 254 3. With the arrow (→) in the center of the dose window, pull the dose knob out in the direction of the arrow until a “0” is seen in the dose window. A dose cannot be dialed until the dose knob is pulled out. 255 4. Turn the dose knob clockwise until your dose is seen in the dose window. If the dose you have dialed is too high, simply turn the dose knob backward until the correct dose is seen in the dose window. 256 5. If you cannot dial your full dose, see the “Questions and Answers” section, Question 5, at the end of this manual. 15 257 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Submission date: 8/4/04 V. Injecting a Dose 258 259 • Always use a new needle for each injection. Storing the Pen with the needle attached 260 may allow insulin to leak from the Pen and air bubbles to form in the cartridge. 261 262 • Caution: Do not attempt to change the dose after you begin to push in the injection 263 button. Failure to follow these instructions carefully may result in getting too much or 264 too little insulin. 265 266 • The effort needed to push in the injection button may increase while you are injecting 267 your insulin dose. If you cannot completely push in the injection button, refer to the 268 “Questions and Answers” section, Question 7, at the end of this manual. 269 270 • Do not inject a dose unless the Pen is primed, just before injection, or you may get too much 271 or too little insulin. 272 273 • If you have set a dose and pushed in the injection button without a needle attached or if no 274 insulin comes out of the needle, see the “Questions and Answers” section, Questions 1 and 2. 275 276 16 277 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Submission date: 8/4/04 V. Injecting a Dose 278 (Continued) 279 280 1. Wash hands. Prepare the skin and use the injection technique recommended by your Health Care Professional. 2. Insert the needle into your skin. Inject the insulin by using your thumb, if possible, to push in the injection button completely. 281 282 3. Keep pressing and continue to hold the injection button firmly while counting slowly to 5. After counting to 5, pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area. 283 284 4. When the injection is done, a diamond (♦) or 285 arrow (→) must be seen in the center of the 286 dose window. This means your full dose has 287 been delivered. If you do not see the diamond 288 or arrow in the center of the dose window, 289 you did not get your full dose. Contact your Health Care Professional for additional 290 instruction. 291 292 293 294 295 296 297 17 298 Correct Correct This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Submission date: 8/4/04 VI. Following an Injection 299 300 301 1. Make sure you got your full dose by checking that the injection button has been completely pushed in and you can see a diamond (♦) or arrow (→) in the center of the dose window. If you do not see the diamond (♦) or arrow (→) in the center of the dose window, you have not received your full dose. Contact your Health Care Professional for additional instructions. 302 2. Carefully replace the outer needle shield as instructed by your Health Care Professional. 303 304 305 306 18 307 Outer Needle Shield This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Submission date: 8/4/04 VI. Following an Injection 308 (Continued) 309 310 3. Remove the capped needle by turning it counterclockwise. Place the used needle in a puncture-resistant disposable container and properly throw it away as directed by your Health Care Professional. 311 4. Replace the cap on the Pen. 312 5. The Pen that you are using should NOT be refrigerated but should be kept at room 313 temperature below 86°F (30°C) and away from direct heat and light. It should be discarded 314 according to the time specified in the “INFORMATION FOR THE PATIENT” insert, even 315 if it still contains insulin. 316 317 Do not store or dispose of the Pen with a needle attached. Storing the Pen with the needle 318 attached may allow insulin to leak from the Pen and air bubbles to form in the cartridge. 319 320 321 19 322 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 Submission date: 8/4/04 323 Questions and Answers 324 325 Problem Action 1. Dose dialed and injection button pushed in without a needle attached. To obtain an accurate dose you must: 1) Attach a new needle. 2) Push in the injection button completely (even if a “0” is seen in the window) until a diamond (♦) or arrow (→) is seen in the center of the dose window. 3) Prime the Pen. 2. Insulin does not come out of the needle. To obtain an accurate dose you must: 1) Attach a new needle. 2) Push in the injection button completely (even if a “0” is seen in the window) until a diamond (♦) or arrow (→) is seen in the center of the dose window. 3) Prime the Pen. See Section III. “Priming the Pen”, pages 10-13. 326 20 327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 Submission date: 8/4/04 Questions and Answers 328 (Continued) 329 330 Problem Action 3. Wrong dose (too high or too low) dialed. If you have not pushed in the injection button, simply turn the dose knob backward or forward to correct the dose. 4. Not sure how much insulin remains in the cartridge. Hold the Pen with the needle end pointing down. The scale (20 units between marks) on the clear cartridge holder shows an estimate of the number of units remaining. These numbers should not be used for measuring an insulin dose. 331 332 21 333 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Submission date: 8/4/04 Questions and Answers 334 (Continued) 335 336 Problem Action 5. Full dose cannot be dialed. The Pen will not allow you to dial a dose greater than the number of insulin units remaining in the cartridge. For example, if you need 31 units and only 25 units remain in the Pen, you will not be able to dial past 25. Do not attempt to dial past this point. (The insulin that remains is unusable and not part of the 300 units.) If a partial dose remains in the Pen you may either: 1) Give the partial dose and then give the remaining dose using a new Pen, or 2) Give the full dose with a new Pen. 6. A small amount of insulin remains in the cartridge but a dose cannot be dialed. The Pen design prevents the cartridge from being completely emptied. The Pen has delivered 300 units of usable insulin. 337 338 22 339 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Submission date: 8/4/04 Questions and Answers 340 (Continued) 341 342 Problem Action 7. Cannot completely push in the injection button when priming the Pen or injecting a dose. 1) Needle is not attached or is clogged. a. Attach a new needle. b. Push in the injection button completely (even if a “0” is seen in the window) until a diamond (♦) or arrow (→) is seen in the center of the dose window. c. Prime the Pen. 2) If you are sure insulin is coming out of the needle, push in the injection button more slowly to reduce the effort needed and maintain a constant pressure until the injection button is completely pushed in. 343 23 344 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 Submission date: 8/4/04 345 For additional information call, 1-800-LillyRx (1-800-545-5979) Literature revised XX 2004 Eli Lilly and Company, Indianapolis, IN 46285, USA 3.0 PV 3734 AMP PRINTED IN USA 346 24 347 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda C-1004 C-1004 If the seal is broken before first use, contact pharmacist If the seal is broken before first use, contact pharmacist A1.0 NL 2493 AMS A1.0 NL 2493 AMS A1.0 NL 2493 AMS NDC 0002-8730-01 Important Please read updated User Manual Every time you inject: Use a new needle Prime to make sure the Pen is ready to dose Make sure you got your full dose disposable insulin delivery device For information call 1-800-545-5979 Eli Lilly and Company Indianapolis, IN 46285, USA 1-800-545-5979 1 " This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:57.812610	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18781s079lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 79}
11,342	Heparin Sodium in 5% Dextrose Injection in Plastic Container VIAFLEX Plus Container (PL 146 Plastic) DESCRIPTION Heparin Sodium in 5% Dextrose Injection is a buffered, sterile, nonpyrogenic solution of Heparin Sodium, USP, derived from porcine intestinal mucosa, standardized for anticoagulant activity, and dextrose in water for injection. Heparin Sodium, USP, is a heterogenous 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) ß-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. The potency of the heparin is determined by biological assay using USP reference standard based upon units of heparin activity per milligram. Structure of Heparin Sodium (representative subunits): Structure of Heparin Sodium (representative subunits) Dextrose Hydrous, USP, is chemically designated D-gluco pyranose monohydrate, a hexose sugar freely soluble in water. It has the following structural formula: 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula The solution is intended for intravenous use only. It contains no antimicrobial agents or bacteriostatic agents. Each 100 mL contains 4,000 or 5,000 or 10,000 USP Heparin Units Heparin Sodium, USP with 5 g Dextrose Hydrous, USP, 103 mg Dibasic Sodium Phosphate Dried, USP (Na2HPO4) and 51 mg Citric Acid Anhydrous, USP (C6H8O7) added as buffers. 20 mg sodium bisulfite is added as a stabilizer. pH 5.5 (5.0 - 6.0). pH may have been adjusted with citric acid and/or sodium hydroxide. Osmolarity 298 mOsmol/L (Actual). This 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 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. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. Peak plasma levels of heparin are achieved 2-4 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. The liver and the reticulo-endothelial system are the sites of biotransformation of heparin. The biphasic elimination curve, a rapidly declining alpha phase (t1/2 = 10 minutes), 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. INDICATIONS AND USAGE Heparin Sodium is indicated for: Anticoagulant therapy in prophylaxis and treatment of venous and arterial thrombosis and its extension; Prophylaxis and treatment of pulmonary embolism; Atrial fibrillation with embolization; Diagnosis and treatment of acute and chronic consumption coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and heart surgery; Prophylaxis and treatment of peripheral arterial embolism. CONTRAINDICATIONS Heparin sodium should not be used in patients: 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda With severe thrombocytopenia; In whom suitable blood coagulation tests - e.g., the whole-blood clotting time, partial thromboplastin time, etc. - cannot be performed at appropriate intervals. With an uncontrollable active bleeding state (see Warnings), except when this is due to disseminated intravascular coagulation. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. 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 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. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 discontinued promptly (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 (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 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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). Other Dextrose solutions 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 bag container label for these solutions bears the statement: Do not administer simultaneously with blood. The intravenous administration of 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 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. Heparin Sodium in 5% Dextrose Injection contains sodium bisulfite, 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. Excessive administration of potassium-free solutions may result in significant hypokalemia. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 in Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. Solutions Containing Dextrose These solutions should be used with caution in patients with overt or subclinical diabetes mellitis. Use of an electronic flow control device is recommended. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. 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. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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, antihistamines, or intravenous nitroglycerin may partially counteract the anticoagulant action of heparin sodium. Drug/Laboratory Tests Interactions Hyperaminotransferasemia Significant elevations of aminotransferase (SGOT [AST] and SGPT [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, rises 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 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. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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). Do not administer unless solution is clear and seal is intact. 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: 1. 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. 2. 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. 3. Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis). See WARNINGS. 9 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 General 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 site 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 [AST] and SGPT [ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Other 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. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 the labeling of Protamine Sulfate Injection, USP products should be consulted. DOSAGE AND ADMINISTRATION Heparin Sodium in 5% Dextrose Injection is for intravenous administration only. 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. 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 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda time is elevated approximately 2.5 to 3 times the control value. Physicians should refer to medical literature. 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 I.V. bolus and 24 hours after the last subcutaneous dose. If continuous I.V. heparin infusion is used, prothrombin time can usually be measured at any time. In converting from heparin to 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 may be used as a guideline for continuous intravenous infusion (based on 150 lb [68 kg] patient): Initial Dose: 5,000 units by I.V. Injection Continuous Dose: 20,000 - 40,000 units/24 hours 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 (I.V., drip) Maintenance Dose: 100 units/kg (I.V., drip) 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. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. All injections in VIAFLEX Plus plastic containers are intended for intravenous administration using sterile equipment. Because dosages of this drug are titrated to response, no additives should be made to Heparin Sodium in 5% Dextrose Injection. HOW SUPPLIED Heparin Sodium in 5% Dextrose Injection in VIAFLEX Plus plastic containers is available as follows: Code Size (mL) NDC Product Name 2B0802 250 0338-0550-02 Heparin Sodium 25,000 Units in 5% Dextrose Injection 2B0808 500 0338-0550-03 Heparin Sodium 25,000 Units in 5% Dextrose Injection 2B0807 500 0338-0549-03 Heparin Sodium 20,000 Units in 5% Dextrose 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. Direction for Use of VIAFLEX Plus Plastic Container 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. 13 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 chamber. If external leaks are found, discard solution as sterility or stability may be impaired. Do not add supplementary medication. Preparation of Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach solution administration set. Refer to complete directions accompanying set. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *Bar Code Position Only 071964110 ©Copyright 1991, 1994, Baxter Healthcare Corporation. All rights reserved. 07-19-64-110 Rev. July 2010 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:57.933866	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018814s032lbl.pdf', 'application_number': 18814, 'submission_type': 'SUPPL ', 'submission_number': 32}
11,330	B1.0NL3055AMP 1 INFORMATION FOR THE PHYSICIAN HUMULIN® R REGULAR U-500 (CONCENTRATED) INSULIN HUMAN INJECTION, USP (rDNA ORIGIN) DESCRIPTION Humulin R® U-500 is a polypeptide hormone structurally identical to human insulin synthesized through rDNA technology in a special non-disease-producing laboratory strain of Escherichia coli bacteria. Humulin R U-500 has the empirical formula C257H383N65O77S6 and a molecular weight of 5808. Humulin R U-500 is a sterile, clear, aqueous and colorless solution that contains human insulin (rDNA origin) 500 units/mL, glycerin 16 mg/mL, metacresol 2.5 mg/mL and zinc oxide to supplement the endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and water for injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH. Humulin R U-500 is for subcutaneous injection only. It should not be used intravenously or intramuscularly. Humulin R U-500 contains 500 units of insulin in each milliliter (5-times more concentrated than Humulin R U-100 [see DOSAGE AND ADMINISTRATION]). It also contains 16 mg glycerin, 2.5 mg metacresol as a preservative, and zinc-oxide calculated to supplement endogenous zinc to obtain a total zinc content of 0.017 mg/100 units and water for injection. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH. Adequate insulin dosage permits patients with diabetes to effectively utilize carbohydrates, proteins and fats. Regardless of dose strength, insulin enables carbohydrate metabolism to occur and thus to prevent the production of ketone bodies by the liver. Some patients might develop severe insulin resistance such that daily doses of several hundred units of insulin or more are required. CLINICAL PHARMACOLOGY Regulation of glucose metabolism is the primary activity of insulin. Insulin lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis, proteolysis, and gluconeogenesis, and enhance protein synthesis and conversion of excess glucose into fat. Administered insulin, including Humulin R U-500, substitutes for inadequate endogenous insulin secretion and partially corrects the disordered metabolism and inappropriate hyperglycemia of diabetes mellitus, which are caused by either a deficiency or a reduction in the biologic effectiveness of insulin. When administered in appropriate doses at prescribed intervals to patients with diabetes mellitus, Humulin R U-500 restores their ability to metabolize carbohydrates, proteins and fats. As with all insulin preparations, the duration of action of Humulin R U-500 is dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin R U-500 is unmodified by any agent that might prolong its action. Clinical experience has shown that it frequently has time action characteristics reflecting both prandial and basal activity. It takes effect within 30 minutes, has a peak similar to that observed with U-100 regular human insulin and has a relatively long duration of activity following a single dose (up to 24 hours) as compared with U-100 regular insulins. This effect has been credited to the high concentration of the preparation. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. INDICATIONS AND USAGE Humulin R U-500 is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 1 and type 2 diabetes mellitus. Humulin R U-500 is useful for the treatment of insulin-resistant patients with diabetes requiring daily doses of more than 200 units, since a large dose may be administered subcutaneously in a reasonable volume. Reference ID: 3632975 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 CONTRAINDICATIONS Humulin R U-500 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Humulin R U-500 or any of its excipients. WARNINGS Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, etc.), species, or method of administration may result in the need for a change in dosage. Humulin R U-500 contains 500 units of insulin in each milliliter (5-times more concentrated than Humulin R U-100). For Humulin R U-500, extreme caution must be observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia. Fluid retention and heart failure with concomitant use of PPAR-gamma agonists: Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including Humulin R U-500, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered. PRECAUTIONS Dosing Confusion/Dosing Errors Medication errors associated with Humulin R U-500 have occurred and resulted in patients experiencing hyperglycemia, hypoglycemia or death. The majority of errors occurred due to errors in dispensing, prescribing or administration. Attention to the following details may prevent: • Dispensing errors The Humulin R U-500 vial, which contains 20 mL, versus the Humulin R U-100 vial, which contains 10 mL – is marked with a band of diagonal brown stripes to distinguish it from the U-100 vial, which has no stripes. “U-500” is also highlighted in red on the label. • Prescribing errors (see DOSAGE AND ADMINISTRATION) The prescribed dose of Humulin R U-500 should always be expressed in actual units of Humulin R U-500 along with corresponding markings on the syringe the patient is using (i.e., a U-100 insulin syringe or tuberculin syringe [see DOSAGE AND ADMINISTRATION]). • Administration errors (see DOSAGE AND ADMINISTRATION) A majority of these errors occurred due to dosing confusion when the Humulin R U-500 dose was prescribed in units or volume corresponding to a U-100 syringe or tuberculin syringe markings, respectively, or the prescribed dose was administered without recognizing that the markings on the syringe used do not directly correspond to U-500 dose. Instructions for use should always be read and followed before use. Instruct the patient to inform hospital or emergency department staff of the dose of Humulin R U-500 prescribed, in the event of a future hospitalization or visit to the Emergency Department. A conversion chart is provided and should always be used when administering Humulin R U-500 doses with U-100 insulin syringes or tuberculin syringes. Hypoglycemia Hypoglycemia is the most common adverse reaction of all insulin therapies, including Humulin R U-500. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with Humulin R U-500. As with all insulin preparations, the time course of Humulin R U-500 action may vary in different individuals or at different times in the same individual and is dependent on dose, site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stresses. Concomitant oral antidiabetic treatment may need to be adjusted. Reference ID: 3632975 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Any patient who requires Humulin R U-500 for control of diabetes should be under close observation until appropriate dosage is established. The response will vary among patients. Most patients will require 2 or 3 injections per day. Insulin resistance, in some patients is transitory; after several weeks or months during which high dosage is required, responsiveness to the pharmacologic effect of insulin may be regained and dosage can be reduced. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia (see PRECAUTIONS, Drug Interactions). As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may prevent a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia may develop 18 to 24 hours after the original injection of Humulin R U-500. Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Non-Ketotic Syndrome Hyperglycemia, diabetic ketoacidosis, or hyperosmolar coma may develop if the patient takes less Humulin R U-500 than needed to control blood glucose levels. This could be due to increases in insulin demand during illness or infection, neglect of diet, omission or improper administration of prescribed insulin doses or use of drugs that affect glucose metabolism or insulin sensitivity. Early signs of diabetic ketoacidosis include glycosuria and ketonuria. Polydipsia, polyuria, loss of appetite, fatigue, dry skin, abdominal pain, nausea and vomiting and compensatory tachypnea come on gradually, usually over a period of some hours or days, in conjunction with hyperglycemia and ketonemia. Severe sustained hyperglycemia may result in hyperosmolar coma or death. Hypokalemia Insulin stimulates potassium movement into the cells, possibly leading to hypokalemia, that left untreated may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). Hypersensitivity and Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Humulin R U-500 (see ADVERSE REACTIONS). Localized reactions and generalized myalgias have been reported with the use of metacresol as an injectable excipient. Renal or Hepatic Impairment Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment. Drug Interactions Some medications may alter insulin requirements and the risk for hypoglycemia and hyperglycemia (see ADVERSE REACTIONS, Drug Interactions). Use in Pregnancy Pregnancy Category B — All pregnancies have background risk of birth defects, miscarriage, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and is decreased with good glucose control. It is important for patients to maintain good control of diabetes before conception and during pregnancy. Special attention should be paid to diet, exercise and insulin regimens. Insulin requirements may decrease during the first trimester, usually increase during the second and third trimesters and rapidly decline after delivery. Careful glucose monitoring is essential in these patients. Female patients should be advised to tell their physician if they intend to become, or if they become pregnant. Studies show that endogenous insulin only crosses the placenta in minimal amounts. While there are no adequate and well-controlled studies in pregnant women, an extensive body of published literature demonstrates the maternal and fetal benefits of insulin treatment in patients with diabetes during Reference ID: 3632975 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 pregnancy. Humulin R U-500 is a recombinant human insulin that is identical to the endogenous hormone; therefore, reproduction and fertility studies were not performed in animals. Labor and Delivery Careful glucose monitoring and management of patients with diabetes during labor and delivery are required. Nursing Mothers Endogenous insulin is present in human milk. Insulin orally ingested is degraded in the gastrointestinal tract. In lactating infants, no adverse reactions have been associated with maternal use of insulin. In a study of eight preterm infants between 26 to 30 weeks gestation, enteral administration of Humulin R did not result in hypoglycemia. Good glucose control supports lactation in patients with diabetes. Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet. Pediatric Use There are no well-controlled studies of use of Humulin R U-500 in children. ADVERSE REACTIONS Hypoglycemia Hypoglycemia is one of the most frequent adverse events experienced by insulin users. Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: • sweating • dizziness • palpitation • tremor • hunger • restlessness • tingling in the hands, feet, lips, or tongue • lightheadedness • inability to concentrate • headache Signs of severe hypoglycemia can include: • disorientation • unconsciousness • death • drowsiness • sleep disturbances • anxiety • blurred vision • slurred speech • depressed mood • irritability • abnormal behavior • unsteady movement • personality changes • seizures • coma Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, autonomic diabetic neuropathy, use of medications such as beta adrenergic blockers, changing insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes. Without recognition of early warning symptoms, the patient may not be able to take steps to avoid more serious hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose more frequently, especially prior to activities such as driving. Mild to moderate hypoglycemia may be treated by eating foods or taking drinks that contain sugar. Patients should always carry a quick source of sugar, such as hard candy, non-diet carbohydrate-containing drinks or glucose tablets. Hypoglycemia when using Humulin R U-500 can be prolonged and severe. Hypokalemia See Precautions Lipodystrophy Administration of insulin subcutaneously can result in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue). Allergy Local Allergy — Patients occasionally experience erythema, local edema, and pruritus at the site of injection. This condition usually is self-limiting. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy (anaphylaxis) may be life threatening. Reference ID: 3632975 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Weight gain Weight gain can occur with some insulin therapies and has been attributed to the anabolic effects of insulin and the decrease in glycosuria. Peripheral Edema Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Drug Interactions The concurrent use of oral antihyperglycemic diabetes agents with Humulin R U-500 is not recommended since there are limited data to support such use. A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring. Drugs that may increase the blood-glucose-lowering effect of Humulin R U-500 and susceptibility to hypoglycemia: • Oral antihyperglycemic diabetes agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors [SSRIs]), pramlintide, disopyramide, fibrates, fluoxetine, propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (e.g., octreotide), and alcohol. Drugs that may reduce the blood-glucose-lowering effect: • Corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents, somatropin, atypical antipsychotics, glucagon, protease inhibitors and thyroid replacement therapy. Drugs that may increase or decrease blood-glucose-lowering effect: • Beta-adrenergic blockers, clonidine, lithium salts, and alcohol. • Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Drugs that may mask the signs of hypoglycemia: • Beta-adrenergic blockers, clonidine, guanethidine, and reserpine. OVERDOSAGE Excess insulin may cause hypoglycemia and hypokalemia. Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately. DOSAGE AND ADMINISTRATION Humulin R U-500 is usually given two or three times daily before meals. The dosage and time of Humulin R U-500 should be individualized and determined, based on the physician’s advice, in accordance with the needs of the patient. The injection of Humulin R U-500 should be followed by a meal within approximately 30 minutes of administration. The average range of total daily insulin requirement for maintenance therapy in insulin-treated patients without severe insulin resistance lies between 0.5 and 1.0 unit/kg/day. However, in pre-pubertal children it usually varies from 0.7 to 1.0 unit/kg/day, but can be much lower during the period of partial remission. In situations of insulin resistance, e.g., during puberty or due to obesity, the daily insulin requirement may be substantially higher. Initial dosages for type 2 diabetes patients are often lower, e.g., 0.2 to 0.4 units/kg/day. Humulin R U-500 is useful for the treatment of insulin resistant patients with diabetes requiring daily doses of more than 200 units, since a large dose may be administered subcutaneously in a reasonable volume. Humulin R U-500 may be administered by subcutaneous injection in the abdominal wall, the thigh, the gluteal region or in the upper arm. Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites. Injection into a lifted skin fold minimizes the risk of intramuscular injection. Injection sites should be rotated within the same region. As with all insulin, the duration of action will vary according to the dose, injection site, blood flow, temperature, and level of physical activity. Reference ID: 3632975 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Humulin R U-500 should only be administered subcutaneously. Do not administer Humulin R U-500 intravenously or intramuscularly. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Never use Humulin R U-500 if it has become viscous (thickened) or cloudy; use it only if it is clear and colorless. Humulin R U-500 should not be used after the printed expiration date. Do not mix Humulin R U-500 with other insulins, as there are no data to support such use. When administering Humulin R U-500 If U-100 insulin syringes are used, since their markings are in units and are designed and intended for use with the less concentrated U-100 insulin products, it is extremely important to explain the amount of Humulin R U-500 insulin to be administered in both actual dose and with specification of “unit markings” on the U-100 syringe. If tuberculin syringes are used, since their markings are in volume (mL), the actual amount of Humulin R U-500 should be explained in both actual dose and with specification of volume (mL). Table 1 contains conversion information using both U-100 insulin and tuberculin syringes to help avoid dose confusion. Table 1: Conversion Information for Humulin R U-500 Insulin Dose When Using a U-100 Insulin Syringe or a Tuberculin Syringe Humulin R U-500 dose (units) U-100 insulin syringe (unit markings) Tuberculin syringe (volume in mL) 25 5 0.05 50 10 0.1 75 15 0.15 100 20 0.2 125 25 0.25 150 30 0.3 175 35 0.35 200 40 0.4 225 45 0.45 250 50 0.5 275 55 0.55 300 60 0.6 325 65 0.65 350 70 0.7 375 75 0.75 400 80 0.8 425 85 0.85 450 90 0.9 475 95 0.95 500 100 1.0 Dose (actual Humulin R U-500 units) Divide dose (actual Humulin R U-500 units) by 5 Divide dose (actual Humulin R U-500 units) by 500 For doses other than those listed above refer to the following formulas: U-100 insulin syringe Divide prescribed Dose (actual units) by 5 = Unit markings in a U-100 insulin syringe. Tuberculin syringe Divide prescribed Dose (actual units) by 500 = Volume (mL) in a tuberculin syringe Storage Not in-use (unopened): Humulin R U-500 vials not in-use should be stored in a refrigerator, (2° to 8°C [36° to 46°F]), but not in the freezer. Reference ID: 3632975 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda B1.0NL3055AMP 7 In-use (opened): The Humulin R U-500 vial currently in-use can be kept unrefrigerated as long as it is kept as cool as possible (below 30°C [86°F]) away from heat and light. In-use vials must be used within 40 days or be discarded, even if they still contain Humulin R U-500. Do not use Humulin R U-500 after the expiration date stamped on the label or if it has been frozen. HOW SUPPLIED Vials, 500 units/mL, 20 mL (HI-500) (1s), NDC 0002-8501-01 Literature revised Month DD, YYYY Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 1996, YYYY, Eli Lilly and Company. All rights reserved. Reference ID: 3632975 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:58.004295	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018780s148lbl.pdf', 'application_number': 18780, 'submission_type': 'SUPPL ', 'submission_number': 148}
11,338	5 10 15 20 25 30 35 40 45 1 1 PV 5713 AMP 2 INFORMATION FOR THE PATIENT 3 4 10 mL Vial (1000 Units per vial) 3 mL Vial (300 Units per vial) HUMULIN® N 6 NPH 7 8 HUMAN INSULIN (rDNA ORIGIN) ISOPHANE SUSPENSION 9 100 UNITS PER ML (U-100) WARNINGS 11 THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE 12 INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN 13 14 PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS. ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY 16 17 18 UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE. 19 21 22 SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS. 23 DIABETES 24 26 Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when the pancreas does not make enough insulin to meet your body’s needs. 27 28 29 31 32 33 34 36 37 To control your diabetes, your doctor has prescribed injections of insulin products to keep your blood glucose at a near-normal level. You have been instructed to test your blood and/or your urine regularly for glucose. Studies have shown that some chronic complications of diabetes such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar is maintained as close to normal as possible. The American Diabetes Association recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may be needed. If your blood tests consistently show below-normal glucose levels, you should also let your doctor know. Proper control of your diabetes requires close and constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by your doctor. 38 39 Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always wear diabetic identification so that appropriate treatment can be given if complications occur away from home. 41 NPH HUMAN INSULIN 42 43 44 46 47 48 Description Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered to produce human insulin. Humulin N [Human insulin (rDNA origin) isophane suspension] is a crystalline suspension of human insulin with protamine and zinc providing an intermediate-acting insulin with a slower onset of action and a longer duration of activity (up to 24 hours) than that of Regular human insulin. The time course of action of any insulin may vary considerably in different individuals or at different times in the Reference ID: 3637811 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 49 same individual. As with all insulin preparations, the duration of action of Humulin N is 50 dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin N 51 is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously 52 or intramuscularly. The concentration of Humulin N is 100 units/mL (U-100). 53 Identification 54 Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has 55 prescribed the type of insulin that he/she believes is best for you. 56 DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND 57 DIRECTION. 58 Always check the carton and the bottle label for the name and letter designation of the insulin 59 you receive from your pharmacy to make sure it is the same as prescribed by your doctor. 60 Always check the appearance of your bottle of Humulin N before withdrawing each dose. 61 Before each injection the Humulin N bottle must be carefully shaken or rotated several times to 62 completely mix the insulin. Humulin N suspension should look uniformly cloudy or milky after 63 mixing. If not, repeat the above steps until contents are mixed. 64 Do not use Humulin N: 65 • if the insulin substance (the white material) remains at the bottom of the bottle after mixing 66 or 67 • if there are clumps in the insulin after mixing, or 68 • if solid white particles stick to the bottom or wall of the bottle, giving a frosted appearance. 69 If you see anything unusual in the appearance of Humulin N suspension in your bottle or notice 70 your insulin requirements changing, talk to your doctor. 71 Storage 72 Not in-use (unopened): Humulin N bottles not in-use should be stored in a refrigerator, but 73 not in the freezer. 74 In-use (opened): The Humulin N bottle you are currently using can be kept unrefrigerated as 75 long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light. 76 Do not use Humulin N after the expiration date stamped on the label or if it has been 77 frozen. 78 INSTRUCTIONS FOR INSULIN VIAL USE 79 NEVER SHARE NEEDLES AND SYRINGES. 80 Correct Syringe Type 81 Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc). 82 With Humulin N, it is important to use a syringe that is marked for U-100 insulin preparations. 83 Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for 84 you, such as a blood glucose level that is too low or too high. 85 Syringe Use 86 To help avoid contamination and possible infection, follow these instructions exactly. 87 Disposable syringes and needles should be used only once and then discarded by placing the 88 used needle in a puncture-resistant disposable container. Properly dispose of the puncture 89 resistant container as directed by your Health Care Professional. 90 Preparing the Dose 91 1. Wash your hands. 92 2. Carefully shake or rotate the bottle of insulin several times to completely mix the insulin. 93 3. Inspect the insulin. Humulin N suspension should look uniformly cloudy or milky. Do not 94 use Humulin N if you notice anything unusual in its appearance. 95 4. If using a new Humulin N bottle, flip off the plastic protective cap, but do not remove the 96 stopper. Wipe the top of the bottle with an alcohol swab. 97 5. If you are mixing insulins, refer to the “Mixing Humulin N and Regular Human Insulin” 98 section below. Reference ID: 3637811 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 99 6. Draw an amount of air into the syringe that is equal to the Humulin N dose. Put the needle 100 through rubber top of the Humulin N bottle and inject the air into the bottle. 101 7. Turn the Humulin N bottle and syringe upside down. Hold the bottle and syringe firmly in 102 one hand and shake gently. 103 8. Making sure the tip of the needle is in the Humulin N suspension, withdraw the correct 104 dose of Humulin N into the syringe. 105 9. Before removing the needle from the Humulin N bottle, check the syringe for air bubbles. 106 If bubbles are present, hold the syringe straight up and tap its side until the bubbles float 107 to the top. Push the bubbles out with the plunger and then withdraw the correct dose. 108 10. Remove the needle from the bottle and lay the syringe down so that the needle does not 109 touch anything. 110 11. If you do not need to mix your Humulin N with Regular human insulin, go to the 111 “Injection Instructions” section below and follow the directions. 112 Mixing Humulin N and Regular Human Insulin (Humulin R) 113 1. Humulin N should be mixed with Humulin R only on the advice of your doctor. 114 2. Draw an amount of air into the syringe that is equal to the amount of Humulin N you are 115 taking. Insert the needle into the Humulin N bottle and inject the air. Withdraw the needle. 116 3. Draw an amount of air into the syringe that is equal to the amount of Humulin R you are 117 taking. Insert the needle into the Humulin R bottle and inject the air, but do not withdraw 118 the needle. 119 4. Turn the Humulin R bottle and syringe upside down. 120 5. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose 121 of Humulin R into the syringe. 122 6. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles. 123 If bubbles are present, hold the syringe straight up and tap its side until the bubbles float 124 to the top. Push the bubbles out with the plunger and then withdraw the correct dose. 125 7. Remove the syringe with the needle from the Humulin R bottle and insert it into the 126 Humulin N bottle. Turn the Humulin N bottle and syringe upside down. Hold the bottle 127 and syringe firmly in one hand and shake gently. Making sure the tip of the needle is in 128 the Humulin N, withdraw the correct dose of Humulin N. 129 8. Remove the needle from the bottle and lay the syringe down so that the needle does not 130 touch anything. 131 9. Follow the directions under “Injection Instructions” section below. 132 Follow your doctor’s instructions on whether to mix your insulins ahead of time or just before 133 giving your injection. It is important to be consistent in your method. 134 Syringes from different manufacturers may vary in the amount of space between the bottom 135 line and the needle. Because of this, do not change: 136 • the sequence of mixing, or 137 • the model and brand of syringe or needle that your doctor has prescribed. 138 Injection Instructions 139 1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the 140 previous injection site. The usual sites of injection are abdomen, thighs, and arms. 141 2. Cleanse the skin with alcohol where the injection is to be made. 142 3. With one hand, stabilize the skin by spreading it or pinching up a large area. 143 4. Insert the needle as instructed by your doctor. 144 5. Push the plunger in as far as it will go. 145 6. Pull the needle out and apply gentle pressure over the injection site for several seconds. 146 Do not rub the area. 147 7. Place the used needle in a puncture-resistant disposable container and properly dispose of 148 the puncture-resistant container as directed by your Health Care Professional. Reference ID: 3637811 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 149 DOSAGE 150 Your doctor has told you which insulin to use, how much, and when and how often to inject it. 151 Because each patient’s diabetes is different, this schedule has been individualized for you. 152 Your usual dose of Humulin N may be affected by changes in your diet, activity, or work 153 schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things 154 that may affect your Humulin N dose are: 155 Illness 156 Illness, especially with nausea and vomiting, may cause your insulin requirements to change. 157 Even if you are not eating, you will still require insulin. You and your doctor should establish a 158 sick day plan for you to use in case of illness. When you are sick, test your blood glucose 159 frequently. If instructed by your doctor, test your ketones and report the results to your doctor. 160 Pregnancy 161 Good control of diabetes is especially important for you and your unborn baby. Pregnancy may 162 make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or 163 are nursing a baby, talk to your doctor. 164 Medication 165 Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising 166 activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin 167 requirements may be reduced in the presence of drugs that lower blood glucose or affect how 168 your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin), 169 sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines. 170 Your Health Care Professional may be aware of other medications that may affect your diabetes 171 control. Therefore, always discuss any medications you are taking with your doctor. 172 Exercise 173 Exercise may lower your body’s need for insulin during and for some time after the physical 174 activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise 175 involves the area of injection site (for example, the leg should not be used for injection just prior 176 to running). Discuss with your doctor how you should adjust your insulin regimen to 177 accommodate exercise. 178 Travel 179 When traveling across more than 2 time zones, you should talk to your doctor concerning 180 adjustments in your insulin schedule. 181 COMMON PROBLEMS OF DIABETES 182 Hypoglycemia (Low Blood Sugar) 183 Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events 184 experienced by insulin users. It can be brought about by: 185 1. Missing or delaying meals. 186 2. Taking too much insulin. 187 3. Exercising or working more than usual. 188 4. An infection or illness associated with diarrhea or vomiting. 189 5. A change in the body’s need for insulin. 190 6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver 191 disease. 192 7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example, 193 aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure 194 medicines. 195 8. Consumption of alcoholic beverages. 196 Symptoms of mild to moderate hypoglycemia may occur suddenly and can include: 197 • sweating • drowsiness 198 • dizziness • sleep disturbances 199 • palpitation • anxiety Reference ID: 3637811 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 200 • tremor 201 • hunger 202 • restlessness 203 • tingling in the hands, feet, lips, or tongue 204 • lightheadedness 205 • inability to concentrate 206 • headache 207 Signs of severe hypoglycemia can include: 208 • disorientation 209 • unconsciousness • blurred vision • slurred speech • depressed mood • irritability • abnormal behavior • unsteady movement • personality changes • seizures • death 210 Therefore, it is important that assistance be obtained immediately. 211 Early warning symptoms of hypoglycemia may be different or less pronounced under certain 212 conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as 213 beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections 214 per day) of diabetes. 215 A few patients who have experienced hypoglycemic reactions after transfer from animal 216 source insulin to human insulin have reported that the early warning symptoms of 217 hypoglycemia were less pronounced or different from those experienced with their 218 previous insulin. 219 Without recognition of early warning symptoms, you may not be able to take steps to avoid 220 more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate 221 hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should 222 monitor their blood glucose frequently, especially prior to activities such as driving. If the blood 223 glucose is below your normal fasting glucose, you should consider eating or drinking sugar 224 containing foods to treat your hypoglycemia. 225 Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar. 226 Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More 227 severe hypoglycemia may require the assistance of another person. Patients who are unable to 228 take sugar orally or who are unconscious require an injection of glucagon or should be treated 229 with intravenous administration of glucose at a medical facility. 230 You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain 231 about these symptoms, you should monitor your blood glucose frequently to help you learn to 232 recognize the symptoms that you experience with hypoglycemia. 233 If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the 234 symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans, 235 and/or exercise programs to help you avoid hypoglycemia. 236 Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA) 237 Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin. 238 Hyperglycemia can be brought about by any of the following: 239 1. Omitting your insulin or taking less than your doctor has prescribed. 240 2. Eating significantly more than your meal plan suggests. 241 3. Developing a fever, infection, or other significant stressful situation. 242 In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in 243 DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually, 244 over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, 245 and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose 246 and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected, 247 prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss 248 of consciousness, or death. Therefore, it is important that you obtain medical assistance 249 immediately. Reference ID: 3637811 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 250 Lipodystrophy 251 Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent 252 depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either 253 of these conditions, talk to your doctor. A change in your injection technique may help alleviate 254 the problem. 255 Allergy 256 Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of 257 injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In 258 some instances, this condition may be related to factors other than insulin, such as irritants in the 259 skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor. 260 Systemic Allergy — Less common, but potentially more serious, is generalized allergy to 261 insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in 262 blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life 263 threatening. If you think you are having a generalized allergic reaction to insulin, call your 264 doctor immediately. 265 ADDITIONAL INFORMATION 266 Information about diabetes may be obtained from your diabetes educator. 267 Additional information about diabetes and Humulin can be obtained by calling The Lilly 268 Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com. 269 Patient Information revised September 2, 2009 270 10 mL Vials manufactured by 271 Eli Lilly and Company, Indianapolis, IN 46285, USA or 272 Lilly France, F-67640 Fegersheim, France 273 3 mL Vials manufactured by 274 Eli Lilly and Company, Indianapolis, IN 46285, USA 275 276 for Eli Lilly and Company, Indianapolis, IN 46285, USA 277 278 Copyright © 1997, 2009, Eli Lilly and Company. All rights reserved. 279 PV 5713 AMP PRINTED IN USA Reference ID: 3637811 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:58.044099	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018781s120lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 120}
11,343	Page 1 LOTRISONE® Cream, USP 1 LOTRISONE® Lotion 2 (clotrimazole, USP and betamethasone dipropionate, USP) 3 FOR TOPICAL USE ONLY, NOT FOR OPHTHALMIC, ORAL, OR 4 INTRAVAGINAL USE, NOT RECOMMENDED FOR PATIENTS UNDER THE 5 AGE OF 17 YEARS AND NOT RECOMMENDED FOR DIAPER DERMATITIS 6 DESCRIPTION LOTRISONE Cream and Lotion contain combinations of 7 clotrimazole, a synthetic antifungal agent, and betamethasone dipropionate, a 8 synthetic corticosteroid, for dermatologic use. 9 Chemically, clotrimazole is 1–(o-chloro-α,α-diphenylbenzyl)imidazole, with the 10 empirical formula C22H17CIN2, a molecular weight of 344.84, and the following 11 structural formula: 12 13 14 15 16 17 18 Clotrimazole is an odorless, white crystalline powder, insoluble in water and 19 soluble in ethanol. 20 Betamethasone dipropionate has the chemical name 9-fluoro-11β,17,21- 21 trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, with the 22 empirical formula C28H37FO7, a molecular weight of 504.59, and the following 23 structural formula: 24 25 26 27 28 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 2 Betamethasone dipropionate is a white to creamy white, odorless crystalline 30 powder, insoluble in water. 31 Each gram of LOTRISONE Cream contains 10 mg clotrimazole and 0.643 mg 32 betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a 33 hydrophilic cream consisting of purified water, mineral oil, white petrolatum, cetyl 34 alcohol plus stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate 35 monobasic monohydrate, and phosphoric acid; benzyl alcohol, as preservative. 36 LORTISONE Cream is smooth, uniform, and white to off-white in color. 37 Each gram of LOTRISONE Lotion contains 10 mg clotrimazole and 0.643 mg 38 betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a 39 hydrophilic base of purified water, mineral oil, white petrolatum, cetyl alcohol plus 40 stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate monobasic 41 monohydrate, and phosphoric acid, benzyl alcohol as a preservative. 42 LOTRISONE Lotion may contain sodium hydroxide. LOTRISONE Lotion is 43 opaque and white in color. 44 CLINICAL PHARMACOLOGY 45 Clotrimazole and Betamethasone Dipropionate 46 LORTISONE Cream has been shown to be least as effective as clottrimazole 47 alone in a different cream vehicle. No comparative studies have been conducted 48 with LOTRISONE Lotion and clotrimazole alone. Use of corticosteroids in the 49 treatment of fungal infection may lead to suppression of host inflammation 50 leading to worsening or decreased cure rate. 51 Clotrimazole 52 Skin penetration and systemic absorption of clotrimazole following topical 53 application of LOTRISONE Cream or Lotion have not been studied. The following 54 information was obtained using 1% clotrimazole cream and solution formulations. 55 Six hours after the application of radioactive clotrimazole 1% cream and 1% 56 solution onto intact and acutely inflamed skin, the concentration of clotrimazole 57 varied from 100 mcg/cm3 in the stratum corneum, to 0.5 to 1 mcg/cm3 in the 58 reticular dermis, and 0.1 mcg/cm3 in the subcutis. No measurable amount of 59 radioactivity (<0.001 mcg/mL) was found in the serum within 48 hours after 60 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 3 application under occlusive dressing of 0.5 mL of the solution or 0.8 g of the 61 cream. Only 0.5% or less of the applied radioactivity was excreted in the urine. 62 Microbiology 63 Mechanism of Action: Clotrimazole is an imidazole antifungal agent. Imidazoles 64 inhibit 14-α-demethylation of lanosterol in fungi by binding to one of the 65 cytochrome P-450 enzymes. This leads to the accumulation of 14-α- 66 methylsterols and reduced concentrations of ergosterol, a sterol essential for a 67 normal fungal cytoplasmic membrane. The methylsterols may affect the electron 68 transport system, thereby inhibiting growth of fungi. 69 Activity In Vivo: Clotrimazole has been shown to be active against most strains of 70 the following dermatophytes, both in vitro and in clinical infections as described in 71 the INDICATIONS AND USAGE section: Epidermophyton floccosum, 72 Trichophyton mentagrophytes, and Trichophyton rubrum. 73 Activity In Vitro: In vitro, clotrimazole has been shown to have activity against 74 most dermatophytes, but the clinical significance of this information is 75 unknown. 76 Drug Resistance: Strains of dermatophytes having a natural resistance to 77 clotrimazole have not been reported. Resistance to azoles including clotrimazole 78 has been reported in some Candida species. 79 No single-step or multiple-step resistance to clotrimazole has developed during 80 successive passages of Trichophyton mentagrophytes. 81 Betamethasone Dipropionate 82 Betamethasone dipropionate, a corticosteroid, has been shown to have topical 83 (dermatologic) and systemic pharmacologic and metabolic effects characteristic 84 of this class of drugs. 85 Pharmacokinetics: The extent of percutaneous absorption of topical 86 corticosteroids is determined by many factors, including the vehicle, the integrity 87 of the epidermal barrier and the use of occlusive dressings. (See DOSAGE AND 88 ADMINISTRATION section). Topical corticosteroids can be absorbed from 89 normal intact skin. Inflammation and/or other disease processes in the skin may 90 increase percutaneous absorption of topical corticosteroids. Occlusive dressings 91 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 substantially increase the percutaneous absorption of topical corticosteroids (See 92 DOSAGE AND ADMINISTRATION section). 93 Once absorbed through the skin, the pharmacokinetics of topical corticosteroids 94 are similar to systemically administered corticosteroids. Corticosteroids are 95 bound to plasma proteins in varying degrees. Corticosteroids are metabolized 96 primarily in the liver and are then excreted by the kidneys. Some of the topical 97 corticosteroids and their metabolites are also excreted into the bile. 98 Studies performed with LOTRISONE Cream and Lotion indicate that these 99 topical combination anti-fungal/corticosteroids may have vasoconstrictor 100 potencies in a range that is comparable to high potency topical corticosteroids. 101 Therefore use is not recommended in patients less than 17 years of age, in 102 diaper dermatitis, and under occlusion. 103 CLINICAL STUDIES (LOTRISONE Cream) 104 In clinical studies of tinea corporis, tinea cruris, and tinea pedis, patients treated 105 with LOTRISONE Cream showed a better clinical response at the first return visit 106 than patients treated with clotrimazole cream. In tinea corporis and tinea cruris, 107 the patient returned 3 to 5 days after starting treatment, and in tinea pedis, after 1 108 week. Mycological cure rates observed in patients treated with LOTRISONE 109 Cream were as good as or better than in those patients treated with clotrimazole 110 cream. In these same clinical studies, patients treated with LORTISONE Cream 111 showed better clinical responses and mycological cure rates when compared 112 with patients treated with betamethasone dipropionate cream. 113 CLINICAL STUDIES (LOTRISONE Lotion) 114 In the treatment of tinea pedis twice daily for four weeks, LOTRISONE Lotion 115 was shown to be superior to vehicle in relieving symptoms of erythema, scaling, 116 pruritus, and maceration at week 2. LOTRISONE Lotion was also shown to have 117 a superior mycological cure rate compared to vehicle two weeks after 118 discontinuation of treatment. It is unclear if the relief of symptoms at 2 weeks in 119 this clinical study with LOTRISONE Lotion was due to the contribution of 120 betamethasone dipropionate, clotrimazole, or both. 121 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 In the treatment of tinea cruris twice daily for two weeks, LOTRISONE Lotion was 122 shown to be superior to vehicle in the relief of symptoms of erythema, scaling, 123 and pruritus after 3 days. It is unclear if the relief of symptoms after 3 days in this 124 clinical study with LOTRISONE Lotion was due to the contribution of 125 betamethasone dipropionate, clotrimazole, or both. 126 The comparative efficacy and safety of LOTRISONE Lotion versus clotrimazole 127 alone in a lotion vehicle have not been studied in the treatment of tinea pedis, 128 tinea cruris, and tinea corporis. The comparative efficacy and safety of 129 LOTRISONE Lotion and LOTRISONE Cream have also not been studied. 130 INDICATIONS AND USAGE 131 LOTRISONE Cream and Lotion are indicated in patients 17 years and older for 132 the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris and 133 tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes, 134 and Trichophyton rubrum. Effective treatment without the risks associated with 135 topical corticosteroid use may be obtained using a topical antifungal agent that 136 does not contain a corticosteroid, especially for noninflammatory tinea infections. 137 The efficacy of LOTRISONE Cream or Lotion for the treatment of infections 138 caused by zoophilic dermatophytes (e.g., Microsporum canis) has not been 139 established. Several cases of treatment failure of Lotrisone Cream in the 140 treatment of infections caused by Microsporum canis have been reported. 141 CONTRAINDICATIONS 142 LOTRISONE Cream or Lotion is contraindicated in patients who are sensitive to 143 clotrimazole, betamethasone dipropionate, other corticosteroids or imidazoles, or 144 to any ingredient in these preparations. 145 PRECAUTIONS 146 General: Systemic absorption of topical corticosteroids can produce reversible 147 hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for 148 glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of 149 Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in 150 some patients by systemic absorption of topical corticosteroids while on 151 treatment. 152 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 Conditions which augment systemic absorption include use over large surface 153 areas, prolonged use, and use under occlusive dressings. Use of more than one 154 corticosteriod-containing product at the same time may increase total systemic 155 glucocorticoid exposure. Patients applying LOTRISONE Cream or Lotion to a 156 large surface area or to areas under occlusion should be evaluated periodically 157 for evidence of HPA-axis suppression. This may be done by using the ACTH 158 stimulation, morning plasma cortisol, and urinary free cortisol tests. 159 If HPA-axis suppression is noted, an attempt should be made to withdraw the 160 drug, to reduce the frequency of application, or to substitute a less potent 161 corticosteroid. Recovery of HPA axis function is generally prompt upon 162 discontinuation of topical corticosteroids. Infrequently, signs and symptoms of 163 glucocorticosteroid insufficiency may occur, requiring supplemental systemic 164 corticosteroids. 165 In a small study, LOTRISONE Cream was applied using large dosages, 7 g daily 166 for 14 days (BID) to the crural area of normal adult subjects. Three of the eight 167 normal subjects on whom LOTRISONE Cream was applied exhibited low 168 morning plasma cortisol levels during treatment. One of these subjects had an 169 abnormal Cortrosyn test. The effect on morning plasma cortisol was transient 170 and subjects recovered one week after discontinuing dosing. In addition, two 171 separate studies in pediatric patients demonstrated adrenal suppression as 172 determined by cosyntropin testing (See PRECAUTIONS – Pediatric Use 173 section). 174 Pediatric patients may be more susceptible to systemic toxicity from equivalent 175 doses due to their larger skin surface to body mass ratios. (See PRECAUTIONS 176 - Pediatric Use section) 177 If irritation develops, LOTRISONE Cream or Lotion should be discontinued and 178 appropriate therapy instituted. 179 THE SAFETY OF LOTRISONE CREAM OR LOTION HAS NOT BEEN 180 DEMONSTRATED IN THE TREATMENT OF DIAPER DERMATITIS. ADVERSE 181 EVENTS CONSISTENT WITH CORTICOSTEROID USE HAVE BEEN 182 OBSERVED IN PATIENTS TREATED WITH LOTRISONE CREAM FOR 183 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 DIAPER DERMATITIS. THE USE OF LOTRISONE CREAM OR LOTION IN 184 THE TREATMENT OF DIAPER DERMATITIS IS NOT RECOMMENDED. 185 Information for Patients: Patients using LOTRISONE Cream or Lotion should 186 receive the following information and instructions: 187 1. The medication is to be used as directed by the physician and is not 188 recommended for use longer than the prescribed time period. It is for 189 external use only. Avoid contact with the eyes, mouth, or intravaginally. 190 2. This medication is to be used for the full prescribed treatment time, even 191 though the symptoms may have improved. Notify the physician if there is no 192 improvement after 1 week of treatment for tinea cruris or tinea corporis, or 193 after 2 weeks for tinea pedis. 194 3. This medication should only be used for the disorder for which it was 195 prescribed. 196 4. Other corticosteriod-containing products should not be used with 197 LOTRISONE without first talking with your physician. 198 5. The treated skin area should not be bandaged, covered, or wrapped so as to 199 be occluded. (See DOSAGE AND ADMINISTRATION section.) 200 6. Any signs of local adverse reactions should be reported to your physician. 201 7. Patients should avoid sources of infection or reinfection. 202 8. When using LOTRISONE Cream or Lotion in the groin area, patients should 203 use the medication for two weeks only, and apply the cream or lotion 204 sparingly. Patients should wear loose-fitting clothing. Notify the physician if 205 the condition persists after 2 weeks. 206 9. The safety of LORTISONE Cream or Lotion has not been demonstrated in the 207 treatment of diaper dermatitis. Adverse events consistent with corticosteroid 208 use have been observed in patients treated with LOTRISONE Cream for 209 diaper dermatitis. The use of LOTRISONE Cream or Lotion in the treatment 210 of diaper dermatitis is not recommended. 211 Laboratory Tests: If there is a lack of response to LOTRISONE Cream or 212 Lotion, appropriate confirmation of the diagnosis, including possible mycological 213 studies, is indicated before instituting another course of therapy. 214 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 The following tests may be helpful in evaluating HPA-axis suppression due to the 215 corticosteroid components: 216 Urinary free cortisol test 217 Morning plasma cortisol test 218 ACTH (cosyntropin) stimulation test 219 Carcinogenesis, Mutagenesis, Impairment of Fertility: There are no adequate 220 laboratory animal studies with either the combination of clotrimazole and 221 betamethasone dipropionate or with either component individually to evaluate 222 carcinogenesis. 223 Betamethasone was negative in the bacterial mutagenicity assay (Salmonella 224 typhimurium and Escherichia coli), and in the mammalian cell mutagenicity assay 225 (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome 226 aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus 227 assay. This pattern of response is similar to that of dexamethasone and 228 hydrocortisone. 229 Reproductive studies with betamethasone dipropionate carried out in rabbits at 230 doses of 1.0 mg/kg by the intramuscular route and in mice up to 33 mg/kg by the 231 intramuscular route indicated no impairment of fertility except for dose-related 232 increases in fetal resorption rates in both species. These doses are 233 approximately 5- and 38- fold the maximum human dose based on body surface 234 areas, respectively. 235 In a combined study of the effects of clotrimazole on fertility, teratogenicity, and 236 postnatal development, male and female rats were dosed orally (diet admixture) 237 with levels of 5, 10, 25, or 50 mg/kg/day (approximately 1-8 times the maximum 238 dose in a 60 kg adult based on body surface area) from 10 weeks prior to mating 239 until 4 weeks postpartum. No adverse effects on the duration of estrous cycle, 240 fertility, or duration of pregnancy were noted. 241 Pregnancy: Teratogenic Effects: Pregnancy Category C: There have been no 242 teratogenic studies performed in animals or humans with the combination of 243 clotrimazole and betamethasone dipropionate. Corticosteriods are generally 244 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 teratogenic in laboratory animals when administered at relatively low dosage 245 levels. 246 Studies in pregnant rats with intravaginal doses up to 100 mg/kg (15 times the 247 maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole 248 exposure. 249 250 No increase in fetal malformations was noted in pregnant rats receiving oral 251 (gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation days 6- 252 15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased 253 resorptions), fetotoxic (reduced fetal weights) and maternally toxic (reduced body 254 weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the 255 maximum human dose) was maternally lethal, and therefore fetuses were not 256 evaluated in this group. Also in this study, doses up to 50 mg/kg/day (8 times the 257 maximum human dose) had no adverse effects on dams or fetuses. However, in 258 the combined fertility, teratogenicity, and postnatal development study described 259 above, 50 mg/kg clotrimazole, was associated with reduced maternal weight gain 260 and reduced numbers of offspring reared to 4 weeks. 261 262 Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day (2-15 times the 263 maximum human dose) were not teratogenic in mice. No evidence of maternal 264 toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120, 265 or 180 mg/kg/day (18-55 times the maximum human dose). 266 267 Betamethasone dipropionate has been shown to be teratogenic in rabbits when 268 given by the intramuscular route at doses of 0.05 mg/kg. This dose is 269 approximately one-fifth the maximum human dose. The abnormalities observed 270 included umbilical hernias, cephalocele and cleft palates. 271 272 Betamethasone dipropionate has not been tested for teratogenic potential by the 273 dermal route of administration. Some corticosteroids have been shown to be 274 teratogenic after dermal application to laboratory animals. 275 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 276 There are no adequate and well-controlled studies in pregnant women of the 277 teratogenic effects of topically applied corticosteroids. Therefore, Lotrisone 278 Cream or Lotion should be used during pregnancy only if the potential benefit 279 justifies the potential risk to the fetus. 280 Nursing Mothers: Systemically administered corticosteroids appear in human 281 milk and could suppress growth, interfere with endogenous corticosteroids 282 production, or cause other untoward effects. It is not known whether topical 283 administration of corticosteroids could result in sufficient systemic absorption to 284 product detectable quantities in human milk. Because many drugs are excreted 285 in human milk, caution should be exercised when LOTRISONE Cream or Lotion 286 is administered to a nursing woman. 287 Pediatric Use: Adverse events consistent with corticosteroid use have been 288 observed in patients under 12 years of age treated with LOTRISONE Cream. In 289 open-label studies, 17 of 43 (39.5%) evaluable pediatric patients (aged 12 to 16 290 years old) using LOTRISONE Cream for treatment of tinea pedis demonstrated 291 adrenal suppression as determined by cosyntropin testing. In another open-label 292 study, 8 of 17 (47.1%) evaluable pediatric patients (aged 12 to 16 years old) 293 using LOTRISONE Cream for treatment of tinea cruris demonstrated adrenal 294 suppression as determined by cosyntropin testing. THE USE OF LOTRISONE 295 CREAM OR LOTION IN THE TREATMENT OF PATIENTS UNDER 17 YEARS 296 OF AGE OR PATIENTS WITH DIAPER DERMATITIS IS NOT 297 RECOMMENDED. 298 Because of higher ratio of skin surface area to body mass, pediatric patients 299 under the age of 12 years are at a higher risk with LOTRISONE Cream or Lotion. 300 The studies described above suggest that pediatric patients under the age of 17 301 years may also have this risk. They are at increased risk of developing Cushing’s 302 syndrome while on treatment and adrenal insufficiency after withdrawal of 303 treatment. Adverse effects, including striae and growth retardation, have been 304 reported with inappropriate use of LOTRISONE Cream in infants and children 305 (see PRECAUTIONS and ADVERSE REACTIONS sections). 306 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, 307 linear growth retardation, delayed weight gain and intracranial hypertension have 308 been reported in children receiving topical corticosteroids. Manifestations of 309 adrenal suppression in children include low plasma cortisol levels and absence of 310 response to ACTH stimulation. Manifestations of intracranial hypertension 311 include bulging fontanelles, headaches, and bilateral papilledema. 312 Geriatric Use: Clinical studies of LOTRISONE Cream or Lotion did not include 313 sufficient numbers of subjects aged 65 and over to determine whether they 314 respond differently from younger subjects. Post-market adverse events reporting 315 for LOTRISONE Cream in patients aged 65 and above includes reports of skin 316 atrophy and rare reports of skin ulceration. Caution should be exercised with the 317 use of these corticosteroid containing topical products on thinning skin. THE USE 318 OF LOTRISONE CREAM OR LOTION UNDER OCCLUSION, SUCH AS IN 319 DIAPER DERMATITIS, IS NOT RECOMMENDED. 320 ADVERSE REACTIONS 321 Adverse reactions reported for LOTRISONE Cream in clinical trials were 322 paresthesia in 1.9% of patients, and rash, edema, and secondary infection, each 323 in 1% of patients. 324 Adverse reactions reported for LOTRISONE Lotion in clinical trials were burning 325 and dry skin in 1.6% of patients and stinging is less than 1% of patients. 326 The following local adverse reactions have been reported with topical 327 corticosteroids and may occur more frequently with the use of occlusive 328 dressings. These reactions are listed in an approximate decreasing order of 329 occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform 330 eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, 331 maceration of the skin, secondary infection, skin atrophy, striae, and miliaria. In 332 the pediatric population, reported adverse events for LOTRISONE Cream include 333 growth retardation, benign intracranial hypertension, Cushing’s syndrome (HPA 334 axis suppression), and local cutaneous reactions, including skin atrophy. 335 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 Systemic absorption of topical corticosteroids has produced reversible 336 hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of 337 Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. 338 Adverse reactions reported with the use of clotrimazole are as follows: erythema, 339 stinging, blistering, peeling, edema, pruritus, urticaria and general irritation of the 340 skin. 341 OVERDOSAGE 342 Amounts greater than 45 g/week of LOTRISONE Cream or 45 mL/week of 343 LOTRISONE Lotion should not be used. Acute overdosage with topical 344 application of LOTRISONE Cream or Lotion is unlikely and would not be 345 expected to lead to life-threatening situation. LOTRISONE Cream or Lotion 346 should not be used for longer than the prescribed time period. 347 348 Topically applied corticosteroids, such as the one contained in LOTRISONE 349 Cream or Lotion can be absorbed in sufficient amounts to produce systemic 350 effects (see PRECAUTIONS section). 351 DOSAGE AND ADMINISTRATION 352 Gently massage sufficient LOTRISONE Cream or Lotion into the affected skin 353 areas twice a day, in the morning and evening. 354 LOTRISONE Cream or Lotion should not be used longer than 2 weeks in 355 the treatment of tinea corporis or tinea cruris, and amounts greater than 45 356 g per week of LOTRISONE Cream or amounts greater than 45 mL per week 357 of LOTRISONE Lotion should not be used. If a patient with tinea corporis or 358 tinea cruris shows no clinical improvement after one week of treatment with 359 LOTRISONE Cream or Lotion, the diagnosis should be reviewed. 360 LOTRISONE Cream or Lotion should not be used longer than 4 weeks in 361 the treatment of tinea pedis and amounts greater than 45 g per week of 362 LOTRISONE Cream or amounts greater than 45 mL per week of 363 LOTRISONE Lotion should not be used. If a patient with tinea pedis shows no 364 clinical improvement after 2 weeks of treatment with LOTRISONE Cream or 365 Lotion, the diagnosis should be reviewed. 366 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 LOTRISONE Cream or Lotion should not be used with occlusive dressings. 367 HOW SUPPLIED 368 LOTRISONE Cream is supplied in 15-gram (NDC 0085-0924-01) and 45-gram 369 tubes (NDC 0085-0924-02); boxes of one. Store between 2°C and 30°C (36°F 370 and 86°F). 371 LOTRISONE Lotion is supplied in 30-mL bottles (NDC 0085-0809-01), box of 372 one. Store at 25°C (77°F) in the upright position only; excursions permitted 373 between 15°C and 30°C (59°F and 86°F). 374 SHAKE WELL BEFORE EACH USE. 375 Rx only 376 Manufactured by: Schering/KEY 377 Schering Corporation/KEY Pharmaceuticals, Inc. 378 Kenilworth, NJ 07033 USA 379 3/10/03 380 Copyright® 2000 Schering Corporation. All Rights reserved. 381 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 TEAR AT PERFORATION 382 GIVE TO PATIENT 383 Patient’s Instructions for Use 384 SHAKE WELL BEFORE EACH USE 385 LOTRISONE® Cream, USP 386 LOTRISONE® Lotion 387 (clotrimazole, USP and betamethasone dipropionate, USP) 388 Patient Information Leaflet 389 What is LOTRISONE Cream or Lotion? 390 LOTRISONE Cream and Lotion are medications used on the skin to treat fungal 391 infections of the feet, groin and body, as diagnosed by your doctor. LOTRISONE 392 Cream or Lotion should be used for fungal infections that are inflamed and have 393 symptoms of redness and/or itching. Talk to your doctor if your fungal infection 394 does not have these symptoms. LOTRISONE Cream and Lotion contain a 395 corticosteroid. Notify your doctor if you notice side effects with the use of 396 LOTRISONE Cream or Lotion (see “What are the possible side effects of 397 LOTRISONE Cream and Lotion?” below). LOTRISONE Cream or Lotion is not 398 to be used in the eyes, in the mouth, or in the vagina. 399 How do LOTRISONE Cream and Lotion Work? 400 LOTRISONE Cream and Lotion are combinations of an antifungal agent 401 (clotrimazole) and a corticosteroid (betamethasone dipropionate). Clotrimazole 402 works against fungus. Betamethasone dipropionate, a corticosteroid, is used to 403 help relieve redness, swelling, itching, and other discomforts of fungal infections. 404 Who should NOT use LOTRISONE Cream or Lotion? 405 LOTRISONE Cream and Lotion are not recommended for use in patients under 406 the age of 17 years. LOTRISONE Cream or Lotion is not recommended for use 407 in diaper rash. 408 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 Patients who are sensitive to clotrimazole and betamethasone dipropionate, 409 other corticosteroids or imidazoles or any ingredients in the preparation should 410 not use LOTRISONE Cream and Lotion. 411 How should I use LOTRISONE Cream or Lotion? 412 Gently message sufficient LOTRISONE Cream or Lotion into the affected and 413 surrounding skin areas twice a day, in the morning and evening. Treatment for 2 414 weeks on the groin or on the body, and for 4 weeks on the feet is recommended. 415 The use of LOTRISONE Cream or Lotion for longer than 4 weeks is not 416 recommended for any condition. Prolonged use of LOTRISONE Cream or Lotion 417 may lead to unwanted side effects. 418 What other important information should I know about LOTRISONE Cream 419 and Lotion? 420 1. This medication is to be used for the full prescribed treatment time, even 421 though the symptoms may have improved. Notify your doctor if there is no 422 improvement after 1 week of treatment on the groin or body or after 2 weeks 423 on the feet. 424 2. This medication should only be used for the disorder for which it was 425 prescribed. 426 3. The treated skin area should not be bandaged or otherwise covered or 427 wrapped. 428 4. Other corticosteriod-containing products should not be used with 429 LOTRISONE without first talking with your physician. 430 5. Any signs of side effects where LOTRISONE Cream or Lotion is applied 431 should be reported to your doctor. 432 6. When using LOTRISONE Cream or Lotion in the groin area, it is especially 433 important to use the medication for two weeks only, and to apply the cream or 434 lotion sparingly. You should tell your doctor if your problem persists after 2 435 weeks. You should also wear loose-fitting clothing so as to avoid tightly 436 covering the area where LOTRISONE Cream is applied. 437 7. This medication is not recommended for use in diaper rash. 438 What are the possible side effects of LOTRISONE Cream and Lotion? 439 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 16 The following side effects have been reported with topical corticosteroid 440 medications: itching, irritation, dryness, infection of the hair follicles, increased 441 hair, acne, change in skin color, allergic skin reaction, skin thinning, and stretch 442 marks. In children, reported adverse events for LOTRISONE Cream include 443 slower growth, Cushing’s syndrome (a type of hormone imbalance that can be 444 very serious), and local skin reactions, including thinning skin and stretch marks. 445 Hormone imbalance (adrenal suppression) was demonstrated in clinical studies 446 in children. 447 Can LOTRISONE Cream or Lotion be used if I am pregnant or plan to 448 become pregnant or if I am nursing? 449 Before using LOTRISONE Cream or Lotion, tell your doctor if you are pregnant 450 or plan to become pregnant. Also, tell your doctor if you are nursing. 451 How should LOTRISONE Cream or Lotion be stored? 452 LOTRISONE Cream should be stored between 2° and 30°C (36° and 86°F). 453 LOTRISONE Lotion should only be stored in an upright position between 15°C 454 and 30°C (59°F and 86°F). Shake well before using LOTRISONE Lotion. 455 General advice about prescription medicines 456 This medicine was prescribed for your particular condition. Only use 457 LOTRISONE Cream or Lotion to treat the condition for which your doctor has 458 prescribed. Do not give LOTRISONE Cream or Lotion to other people. It may 459 harm them. 460 This leaflet summarizes the most important information about LOTRISONE 461 Cream and Lotion. If you would like more information, talk with your doctor. You 462 can ask your pharmacist or doctor for information about LOTRISONE Cream and 463 Lotion that is written for health professionals. 464 Rx only 465 Schering/Key 466 Schering Corporation/Key Pharmaceuticals 467 Kenilworth, NJ 07033 468 Copyright 2000, Schering Corp. All rights reserved. 469 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 17 3/10/03 470 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:58.395884	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18827slr025_lotrisone_lbl.pdf', 'application_number': 18827, 'submission_type': 'SUPPL ', 'submission_number': 25}
11,345	LOTRISONE® Cream LOTRISONE® Lotion (clotrimazole and betamethasone dipropionate) FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. NOT RECOMMENDED FOR PATIENTS UNDER THE AGE OF 17 YEARS AND NOT RECOMMENDED FOR DIAPER DERMATITIS. DESCRIPTION LOTRISONE® Cream and Lotion contain combinations of clotrimazole, a synthetic antifungal agent, and betamethasone dipropionate, a synthetic corticosteroid, for dermatologic use. Chemically, clotrimazole is 1–(o-chloro-α,α-diphenylbenzyl) imidazole, with the empirical formula C22H17CIN2, a molecular weight of 344.84, and the following structural formula: Chemical structure of clotrimazole Clotrimazole is an odorless, white crystalline powder, insoluble in water and soluble in ethanol. Betamethasone dipropionate has the chemical name 9-fluoro-11β,17,21 trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, with the empirical formula C28H37FO7, a molecular weight of 504.59, and the following structural formula: Chemical Structure of Betamethasone dipropionate 1 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Betamethasone dipropionate is a white to creamy white, odorless crystalline powder, insoluble in water. Each gram of LOTRISONE Cream contains 10 mg clotrimazole and 0.643 mg betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a hydrophilic cream consisting of purified water, mineral oil, white petrolatum, cetyl alcohol plus stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate monobasic monohydrate, and phosphoric acid; benzyl alcohol as preservative. LOTRISONE Cream may contain sodium hydroxide. LOTRISONE Cream is smooth, uniform, and white to off-white in color. Each gram of LOTRISONE Lotion contains 10 mg clotrimazole and 0.643 mg betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a hydrophilic base of purified water, mineral oil, white petrolatum, cetyl alcohol plus stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate monobasic monohydrate, and phosphoric acid; benzyl alcohol as a preservative. LOTRISONE Lotion may contain sodium hydroxide. LOTRISONE Lotion is opaque and white in color. CLINICAL PHARMACOLOGY Clotrimazole and Betamethasone Dipropionate LOTRISONE® Cream has been shown to be at least as effective as clotrimazole alone in a different cream vehicle. No comparative studies have been conducted with LOTRISONE® Lotion and clotrimazole alone. Use of corticosteroids in the treatment of a fungal infection may lead to suppression of host inflammation leading to worsening or decreased cure rate. Clotrimazole Skin penetration and systemic absorption of clotrimazole following topical application of LOTRISONE Cream or Lotion have not been studied. The following information was obtained using 1% clotrimazole cream and solution formulations. Six hours after the application of radioactive clotrimazole 1% cream and 1% solution onto intact and acutely inflamed skin, the concentration of clotrimazole varied from 100 mcg/cm3 in the stratum corneum, to 0.5 to 1 mcg/cm3 in the reticular dermis, and 0.1 mcg/cm3 in the subcutis. No measurable amount of radioactivity (<0.001 mcg/mL) was found in the serum within 48 hours after application under occlusive dressing of 0.5 mL of the solution or 0.8 g of the cream. Only 0.5% or less of the applied radioactivity was excreted in the urine. Microbiology Mechanism of Action: Clotrimazole is an imidazole antifungal agent. Imidazoles inhibit 14-α-demethylation of lanosterol in fungi by binding to one of the cytochrome P-450 enzymes. This leads to the accumulation of 14-α methylsterols and reduced concentrations of ergosterol, a sterol essential for a 2 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda normal fungal cytoplasmic membrane. The methylsterols may affect the electron transport system, thereby inhibiting growth of fungi. Activity In Vivo: Clotrimazole has been shown to be active against most strains of the following dermatophytes, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section: Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum. Activity In Vitro: In vitro, clotrimazole has been shown to have activity against many dermatophytes, but the clinical significance of this information is unknown. Drug Resistance: Strains of dermatophytes having a natural resistance to clotrimazole have not been reported. Resistance to azoles including clotrimazole has been reported in some Candida species. No single-step or multiple-step resistance to clotrimazole has developed during successive passages of Trichophyton mentagrophytes. Betamethasone Dipropionate Betamethasone dipropionate, a corticosteroid, has been shown to have topical (dermatologic) and systemic pharmacologic and metabolic effects characteristic of this class of drugs. Pharmacokinetics The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier and the use of occlusive dressings (see DOSAGE AND ADMINISTRATION). Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption of topical corticosteroids. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids (see DOSAGE AND ADMINISTRATION). Once absorbed through the skin, the pharmacokinetics of topical corticosteroids are similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. Studies performed with LOTRISONE Cream and Lotion indicate that these topical combination antifungal/corticosteroids may have vasoconstrictor potencies in a range that is comparable to high-potency topical corticosteroids. Therefore, use is not recommended in patients less than 17 years of age, in diaper dermatitis, and under occlusion. 3 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL STUDIES (LOTRISONE® Cream) In clinical studies of tinea corporis, tinea cruris, and tinea pedis, patients treated with LOTRISONE Cream showed a better clinical response at the first return visit than patients treated with clotrimazole cream. In tinea corporis and tinea cruris, the patient returned 3 to 5 days after starting treatment, and in tinea pedis, after 1 week. Mycological cure rates observed in patients treated with LOTRISONE Cream were as good as or better than in those patients treated with clotrimazole cream. In these same clinical studies, patients treated with LOTRISONE Cream showed better clinical responses and mycological cure rates when compared with patients treated with betamethasone dipropionate cream. CLINICAL STUDIES (LOTRISONE® Lotion) In the treatment of tinea pedis twice daily for 4 weeks, LOTRISONE Lotion was shown to be superior to vehicle in relieving symptoms of erythema, scaling, pruritus, and maceration at Week 2. LOTRISONE Lotion was also shown to have a superior mycological cure rate compared to vehicle 2 weeks after discontinuation of treatment. It is unclear if the relief of symptoms at 2 weeks in this clinical study with LOTRISONE Lotion was due to the contribution of betamethasone dipropionate, clotrimazole, or both. In the treatment of tinea cruris twice daily for 2 weeks, LOTRISONE Lotion was shown to be superior to vehicle in the relief of symptoms of erythema, scaling, and pruritus after 3 days. It is unclear if the relief of symptoms after 3 days in this clinical study with LOTRISONE Lotion was due to the contribution of betamethasone dipropionate, clotrimazole, or both. The comparative efficacy and safety of LOTRISONE Lotion versus clotrimazole alone in a lotion vehicle have not been studied in the treatment of tinea pedis or tinea cruris or tinea corporis. The comparative efficacy and safety of LOTRISONE Lotion and LOTRISONE® Cream have also not been studied. INDICATIONS AND USAGE LOTRISONE® Cream and Lotion are indicated in patients 17 years and older for the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris, and tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum. Effective treatment without the risks associated with topical corticosteroid use may be obtained using a topical antifungal agent that does not contain a corticosteroid, especially for noninflammatory tinea infections. The efficacy of LOTRISONE Cream or Lotion for the treatment of infections caused by zoophilic dermatophytes (eg, Microsporum canis) has not been established. Several cases of treatment failure of LOTRISONE Cream in the treatment of infections caused by Microsporum canis have been reported. 4 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS LOTRISONE® Cream or Lotion is contraindicated in patients who are sensitive to clotrimazole, betamethasone dipropionate, other corticosteroids or imidazoles, or to any ingredient in these preparations. PRECAUTIONS General Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Conditions which augment systemic absorption include use over large surface areas, prolonged use, and use under occlusive dressings. Use of more than one corticosteroid-containing product at the same time may increase total systemic glucocorticoid exposure. Patients applying LOTRISONE® Cream or Lotion to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, morning plasma cortisol, and urinary-free cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. In a small study, LOTRISONE Cream was applied using large dosages, 7 g daily for 14 days (BID) to the crural area of normal adult subjects. Three of the eight normal subjects on whom LOTRISONE Cream was applied exhibited low morning plasma cortisol levels during treatment. One of these subjects had an abnormal Cortrosyn test. The effect on morning plasma cortisol was transient and subjects recovered 1 week after discontinuing dosing. In addition, two separate studies in pediatric patients demonstrated adrenal suppression as determined by cosyntropin testing (see PRECAUTIONS, Pediatric Use section). Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONS, Pediatric Use section). If irritation develops, LOTRISONE Cream or Lotion should be discontinued and appropriate therapy instituted. 5 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda THE SAFETY OF LOTRISONE CREAM OR LOTION HAS NOT BEEN DEMONSTRATED IN THE TREATMENT OF DIAPER DERMATITIS. ADVERSE EVENTS CONSISTENT WITH CORTICOSTEROID USE HAVE BEEN OBSERVED IN PATIENTS TREATED WITH LOTRISONE CREAM FOR DIAPER DERMATITIS. THE USE OF LOTRISONE CREAM OR LOTION IN THE TREATMENT OF DIAPER DERMATITIS IS NOT RECOMMENDED. Information for Patients Patients using LOTRISONE Cream or Lotion should receive the following information and instructions: 1. The medication is to be used as directed by the physician and is not recommended for use longer than the prescribed time period. It is for external use only. Avoid contact with the eyes, the mouth, or intravaginally. 2. This medication is to be used for the full prescribed treatment time, even though the symptoms may have improved. Notify the physician if there is no improvement after 1 week of treatment for tinea cruris or tinea corporis, or after 2 weeks for tinea pedis. 3. This medication should only be used for the disorder for which it was prescribed. 4. Other corticosteroid-containing products should not be used with LOTRISONE without first talking with your physician. 5. The treated skin area should not be bandaged, covered, or wrapped so as to be occluded (see DOSAGE AND ADMINISTRATION). 6. Any signs of local adverse reactions should be reported to your physician. 7. Patients should avoid sources of infection or reinfection. 8. When using LOTRISONE Cream or Lotion in the groin area, patients should use the medication for 2 weeks only, and apply the cream or lotion sparingly. Patients should wear loose-fitting clothing. Notify the physician if the condition persists after 2 weeks. 9. The safety of LOTRISONE Cream or Lotion has not been demonstrated in the treatment of diaper dermatitis. Adverse events consistent with corticosteroid use have been observed in patients treated with LOTRISONE Cream for diaper dermatitis. The use of LOTRISONE Cream or Lotion in the treatment of diaper dermatitis is not recommended. 6 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests If there is a lack of response to LOTRISONE Cream or Lotion, appropriate confirmation of the diagnosis, including possible mycological studies, is indicated before instituting another course of therapy. The following tests may be helpful in evaluating HPA axis suppression due to the corticosteroid components: Urinary-free cortisol test Morning plasma cortisol test ACTH (cosyntropin) stimulation test Carcinogenesis, Mutagenesis, Impairment of Fertility There are no adequate laboratory animal studies with either the combination of clotrimazole and betamethasone dipropionate or with either component individually to evaluate carcinogenesis. Betamethasone was negative in the bacterial mutagenicity assay (Salmonella typhimurium and Escherichia coli) and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay. This pattern of response is similar to that of dexamethasone and hydrocortisone. Reproductive studies with betamethasone dipropionate carried out in rabbits at doses of 1.0 mg/kg by the intramuscular route and in mice up to 33 mg/kg by the intramuscular route indicated no impairment of fertility except for dose-related increases in fetal resorption rates in both species. These doses are approximately 5- and 38-fold the maximum human dose based on body surface areas, respectively. In a combined study of the effects of clotrimazole on fertility, teratogenicity, and postnatal development, male and female rats were dosed orally (diet admixture) with levels of 5, 10, 25, or 50 mg/kg/day (approximately 1-8 times the maximum dose in a 60-kg adult based on body surface area) from 10 weeks prior to mating until 4 weeks postpartum. No adverse effects on the duration of estrous cycle, fertility, or duration of pregnancy were noted. Pregnancy Teratogenic Effects Pregnancy Category C There have been no teratogenic studies performed in animals or humans with the combination of clotrimazole and betamethasone dipropionate. Corticosteroids are generally teratogenic in laboratory animals when administered at relatively low dosage levels. 7 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies in pregnant rats with intravaginal doses up to 100 mg/kg (15 times the maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole exposure. No increase in fetal malformations was noted in pregnant rats receiving oral (gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation Days 6 to 15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased resorptions), fetotoxic (reduced fetal weights), and maternally toxic (reduced body weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the maximum human dose) was maternally lethal, and therefore fetuses were not evaluated in this group. Also in this study, doses up to 50 mg/kg/day (8 times the maximum human dose) had no adverse effects on dams or fetuses. However, in the combined fertility, teratogenicity, and postnatal development study described above, 50 mg/kg clotrimazole, was associated with reduced maternal weight gain and reduced numbers of offspring reared to 4 weeks. Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day (2-15 times the maximum human dose) were not teratogenic in mice. No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120, or 180 mg/kg/day (18-55 times the maximum human dose). Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. This dose is approximately one-fifth the maximum human dose. The abnormalities observed included umbilical hernias, cephalocele, and cleft palates. Betamethasone dipropionate has not been tested for teratogenic potential by the dermal route of administration. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals. There are no adequate and well-controlled studies in pregnant women of the teratogenic effects of topically applied corticosteroids. Therefore, LOTRISONE Cream or Lotion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOTRISONE Cream or Lotion is administered to a nursing woman. 8 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Adverse events consistent with corticosteroid use have been observed in patients under 12 years of age treated with LOTRISONE Cream. In open-label studies, 17 of 43 (39.5%) evaluable pediatric patients (aged 12 - 16 years old) using LOTRISONE Cream for treatment of tinea pedis demonstrated adrenal suppression as determined by cosyntropin testing. In another open-label study, 8 of 17 (47.1%) evaluable pediatric patients (aged 12 - 16 years old) using LOTRISONE Cream for treatment of tinea cruris demonstrated adrenal suppression as determined by cosyntropin testing. THE USE OF LOTRISONE CREAM OR LOTION IN THE TREATMENT OF PATIENTS UNDER 17 YEARS OF AGE OR PATIENTS WITH DIAPER DERMATITIS IS NOT RECOMMENDED. Because of higher ratio of skin surface area to body mass, pediatric patients under the age of 12 years are at a higher risk with LOTRISONE Cream or Lotion. The studies described above suggest that pediatric patients under the age of 17 years may also have this risk. They are at increased risk of developing Cushing’s syndrome while on treatment and adrenal insufficiency after withdrawal of treatment. Adverse effects, including striae and growth retardation, have been reported with inappropriate use of LOTRISONE Cream in infants and children (see PRECAUTIONS and ADVERSE REACTIONS). Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Geriatric Use Clinical studies of LOTRISONE Cream and Lotion did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Postmarket adverse event reporting for LOTRISONE Cream in patients aged 65 and above includes reports of skin atrophy and rare reports of skin ulceration. Caution should be exercised with the use of these corticosteroid-containing topical products on thinning skin. THE USE OF LOTRISONE CREAM OR LOTION UNDER OCCLUSION, SUCH AS IN DIAPER DERMATITIS, IS NOT RECOMMENDED. ADVERSE REACTIONS Adverse reactions reported for LOTRISONE® Cream in clinical trials were paresthesia in 1.9% of patients, and rash, edema, and secondary infection, each in less than 1% of patients. 9 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse reactions reported for LOTRISONE® Lotion in clinical trials were burning and dry skin in 1.6% of patients and stinging in less than 1% of patients. The following local adverse reactions have been reported with topical corticosteroids and may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, miliaria, capillary fragility (ecchymoses), telangiectasia, and sensitization (local reactions upon repeated application of product). In the pediatric population, reported adverse events for LOTRISONE Cream include growth retardation, benign intracranial hypertension, Cushing’s syndrome (HPA axis suppression), and local cutaneous reactions, including skin atrophy. Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Adverse reactions reported with the use of clotrimazole are as follows: erythema, stinging, blistering, peeling, edema, pruritus, urticaria, and general irritation of the skin. OVERDOSAGE Amounts greater than 45 g/week of LOTRISONE® Cream or 45 mL/week of LOTRISONE® Lotion should not be used. Acute overdosage with topical application of LOTRISONE Cream or Lotion is unlikely and would not be expected to lead to a life-threatening situation. LOTRISONE Cream or Lotion should not be used for longer than the prescribed time period. Topically applied corticosteroids, such as the one contained in LOTRISONE Cream or Lotion can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS). DOSAGE AND ADMINISTRATION Gently massage sufficient LOTRISONE® Cream or Lotion into the affected skin areas twice a day, in the morning and evening. LOTRISONE Cream or Lotion should not be used longer than 2 weeks in the treatment of tinea corporis or tinea cruris, and amounts greater than 45 g per week of LOTRISONE Cream or amounts greater than 45 mL per week of LOTRISONE Lotion should not be used. If a patient with tinea corporis or tinea cruris shows no clinical improvement after 1 week of treatment with LOTRISONE Cream or Lotion, the diagnosis should be reviewed. 10 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LOTRISONE Cream or Lotion should not be used longer than 4 weeks in the treatment of tinea pedis and amounts greater than 45 g per week of LOTRISONE Cream or amounts greater than 45 mL per week of LOTRISONE Lotion should not be used. If a patient with tinea pedis shows no clinical improvement after 2 weeks of treatment with LOTRISONE Cream or Lotion, the diagnosis should be reviewed. LOTRISONE Cream or Lotion should not be used with occlusive dressings. HOW SUPPLIED LOTRISONE® Cream is supplied in 15-g (NDC 0085-0924-01) and 45-g tubes (NDC 0085-0924-02); boxes of one. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. LOTRISONE® Lotion is supplied in 30-mL bottles (NDC 0085-0809-01), box of one. Store at 25°C (77°F) in the upright position only; excursions permitted between 15°C and 30°C (59°F and 86°F). SHAKE LOTION WELL BEFORE EACH USE. Rx only Schering Corporation Kenilworth, NJ 07033 USA Revised. May 2009 Copyright © 2000, 2007, Schering Corporation. All rights reserved. 11 LRN# 000370-LOS-MTL-USPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LOTRISONE® Cream LOTRISONE® Lotion (clotrimazole and betamethasone dipropionate) Patient’s Instructions for Use SHAKE LOTION WELL BEFORE EACH USE Patient Information Leaflet What is LOTRISONE® Cream or Lotion? LOTRISONE Cream and Lotion are medications used on the skin to treat fungal infections of the feet, groin, and body, as diagnosed by your doctor. LOTRISONE Cream or Lotion should be used for fungal infections that are inflamed and have symptoms of redness and/or itching. Talk to your doctor if your fungal infection does not have these symptoms. LOTRISONE Cream and Lotion contain a corticosteroid. Notify your doctor if you notice side effects with the use of LOTRISONE Cream or Lotion (see “What are the possible side effects of LOTRISONE Cream and Lotion?” below). LOTRISONE Cream or Lotion is not to be used in the eyes, in the mouth, or in the vagina. How do LOTRISONE® Cream and Lotion work? LOTRISONE Cream and Lotion are combinations of an antifungal agent (clotrimazole) and a corticosteroid (betamethasone dipropionate). Clotrimazole works against fungus. Betamethasone dipropionate, a corticosteroid, is used to help relieve redness, swelling, itching, and other discomforts of fungal infections. Who should NOT use LOTRISONE® Cream or Lotion? LOTRISONE Cream and Lotion are not recommended for use in patients under the age of 17 years. LOTRISONE Cream or Lotion is not recommended for use in diaper rash. Patients who are sensitive to clotrimazole and betamethasone dipropionate, other corticosteroids or imidazoles, or any ingredients in the preparation should not use LOTRISONE Cream and Lotion. How should I use LOTRISONE® Cream or Lotion? Gently massage sufficient LOTRISONE Cream or Lotion into the affected and surrounding skin areas twice a day, in the morning and evening. Treatment for 2 weeks on the groin or on the body, and for 4 weeks on the feet is recommended. The use of LOTRISONE Cream or Lotion for longer than 4 weeks is not 1 LRN# 000370-LOS-MTL-PPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda recommended for any condition. Prolonged use of LOTRISONE Cream or Lotion may lead to unwanted side effects. What other important information should I know about LOTRISONE® Cream and Lotion? 1. This medication is to be used for the full prescribed treatment time, even though the symptoms may have improved. Notify your doctor if there is no improvement after 1 week of treatment on the groin or body or after 2 weeks on the feet. 2. This medication should only be used for the disorder for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped. 4. Other corticosteroid-containing products should not be used with LOTRISONE without first talking with your physician. 5. Any signs of side effects where LOTRISONE Cream or Lotion is applied should be reported to your doctor. 6. When using LOTRISONE Cream or Lotion in the groin area, it is especially important to use the medication for 2 weeks only, and to apply the cream or lotion sparingly. You should tell your doctor if your problem persists after 2 weeks. You should also wear loose-fitting clothing so as to avoid tightly covering the area where LOTRISONE Cream or Lotion is applied. 7. This medication is not recommended for use in diaper rash. What are the possible side effects of LOTRISONE® Cream and Lotion? The following side effects have been reported with topical corticosteroid medications: itching, irritation, dryness, infection of the hair follicles, increased hair, acne, fragile blood vessels, spider veins, sensitization (local reactions upon repeated application of product), change in skin color, allergic skin reaction, skin thinning, and stretch marks. In children, reported adverse events for LOTRISONE Cream include slower growth, Cushing’s syndrome (a type of hormone imbalance that can be very serious), and local skin reactions, including thinning skin and stretch marks. Hormone imbalance (adrenal suppression) was demonstrated in clinical studies in children. Can LOTRISONE® Cream or Lotion be used if I am pregnant or plan to become pregnant or if I am nursing? Before using LOTRISONE Cream or Lotion, tell your doctor if you are pregnant or plan to become pregnant. Also, tell your doctor if you are nursing. How should LOTRISONE® Cream or Lotion be stored? LOTRISONE Cream should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. 2 LRN# 000370-LOS-MTL-PPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LOTRISONE Lotion should be stored at 25°C (77°F) in the upright position only; excursions permitted between 15°C and 30°C (59°F and 86°F). Shake well before using LOTRISONE Lotion. General advice about prescription medicines This medicine was prescribed for your particular condition. Only use LOTRISONE® Cream or Lotion to treat the condition for which your doctor has prescribed. Do not give LOTRISONE Cream or Lotion to other people. It may harm them. This leaflet summarizes the most important information about LOTRISONE Cream and Lotion. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about LOTRISONE Cream and Lotion that is written for health professionals. Rx only Schering Corporation Kenilworth, NJ 07033 USA Copyright © 2000, 2007, Schering Corporation. All rights reserved. Rev. May 2009 3 LRN# 000370-LOS-MTL-PPI-2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:58.423877	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018827s042lbl.pdf', 'application_number': 18827, 'submission_type': 'SUPPL ', 'submission_number': 42}
11,346	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LOTRISONE cream safely and effectively. See full prescribing information for LOTRISONE cream. LOTRISONE® (clotrimazole and betamethasone dipropionate) cream, 1%/0.05%, for topical use Initial U.S. Approval: 1984 ----------------------------INDICATIONS AND USAGE --------------------------- LOTRISONE cream contains a combination of clotrimazole, an azole antifungal, and betamethasone dipropionate, a corticosteroid, and is indicated for the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris, and tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum in patients 17 years and older. (1) ---------------------- DOSAGE AND ADMINISTRATION ---------------------- • Tinea pedis: Apply a thin film to the affected skin areas twice a day for 2 weeks. (2) • Tinea cruris and tinea corporis: Apply a thin film to the affected skin area twice a day for 1 week. (2) • LOTRISONE cream should not be used longer than 2 weeks in the treatment of tinea corporis or tinea cruris, and longer than 4 weeks in the treatment of tinea pedis. (2) • Do not use with occlusive dressings unless directed by a physician. (2) • Not for ophthalmic, oral or intravaginal use. (2) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Cream, 1%/0.05% (3) Each gram of LOTRISONE cream contains 10 mg of clotrimazole and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone) (3) -------------------------------CONTRAINDICATIONS ------------------------------ None. (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------- • LOTRISONE cream can cause reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency during and after withdrawal of the treatment. Risk factor(s) are: use of high-potency topical corticosteroid, use over a large surface area or to areas under occlusion, prolonged use, altered skin barrier, liver failure, and young age. Modify use should HPA axis suppression develop. (5.1, 8.4) • Pediatric patients may be more susceptible to systemic toxicity. (5.1, 8.4) • The use of LOTRISONE cream in the treatment of diaper dermatitis is not recommended. (5.2) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions reported for LOTRISONE cream were paraesthesia in 1.9% of patients and rash, edema, and secondary infections each in less than 1% of patients. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877 888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 4/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Effects on Endocrine System 5.2 Diaper Dermatitis 6 ADVERSE REACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION Reference ID: 3490830 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 INDICATIONS AND USAGE LOTRISONE cream is a combination of an azole antifungal and corticosteroid and is indicated for the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris, and tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum in patients 17 years and older. 2 DOSAGE AND ADMINISTRATION Treatment of tinea corporis or tinea cruris: • Apply a thin film of LOTRISONE cream into the affected skin areas twice a day for one week. • Do not use more than 45 grams per week. Do not use with occlusive dressings. • If a patient shows no clinical improvement after 1 week of treatment with LOTRISONE cream, the diagnosis should be reviewed. • Do not use longer than 2 weeks. Treatment of tinea pedis: • Gently massage a sufficient amount of LOTRISONE cream into the affected skin areas twice a day for two weeks. • Do not use more than 45 grams per week. Do not use with occlusive dressings. • If a patient shows no clinical improvement after 2 week of treatment with LOTRISONE cream, the diagnosis should be reviewed. • Do not use longer than 4 weeks. LOTRISONE cream is for topical use only. It is not for oral, ophthalmic, or intravaginal use. 3 DOSAGE FORMS AND STRENGTHS Cream, 1%/0.05%. Each gram of LOTRISONE cream contains 10 mg of clotrimazole and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone) in a white to off-white cream base. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Effects on Endocrine System LOTRISONE cream can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or after withdrawal of treatment. Cushing’s syndrome and hyperglycemia may also occur due to the systemic effect of corticosteroids while on treatment. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressing, altered skin barrier, liver failure, and young age. Because of the potential for systemic corticosteroid effects, patients may need to be periodically evaluated for HPA axis suppression. This may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. In a small trial, LOTRISONE cream was applied using large dosages, 7 g daily for 14 days (BID) to the crural area of normal adult subjects. Three of the 8 normal subjects on whom LOTRISONE cream was applied exhibited low morning plasma cortisol levels during treatment. One of these subjects had an abnormal cosyntropin test. The effect on morning plasma cortisol was transient and subjects recovered 1 week after discontinuing dosing. In addition, 2 separate trials in pediatric subjects demonstrated adrenal suppression as determined by cosyntropin testing [see Use in Specific Populations (8.4)]. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. Pediatric patients may be more susceptible to systemic toxicity due to their larger skin-surface-to-body mass ratios [see Use in Specific Populations (8.4)]. 5.2 Diaper Dermatitis The use of LOTRISONE cream in the treatment of diaper dermatitis is not recommended. 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Reference ID: 3490830 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In clinical trials common adverse reaction reported for LOTRISONE cream was paresthesia in 1.9% of patients. Adverse reactions reported at a frequency < 1% included rash, edema, and secondary infection. 6.2 Postmarketing Experience Because adverse 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 local adverse reactions have been reported with topical corticosteroids: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, skin atrophy, striae, miliaria, capillary fragility (ecchymoses), telangiectasia, and sensitization (local reactions upon repeated application of product). Adverse reactions reported with the use of clotrimazole are: erythema, stinging, blistering, peeling, edema, pruritus, urticaria, and general irritation of the skin. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic effects, Pregnancy Category C There are no adequate and well-controlled studies with LOTRISONE cream in pregnant women. Therefore, LOTRISONE cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There have been no teratogenic studies performed in animals or humans with the combination of clotrimazole and betamethasone dipropionate. Corticosteroids are generally teratogenic in laboratory animals when administered at relatively low dosage levels. Studies in pregnant rats with intravaginal doses up to 100 mg/kg (15 times the maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole exposure. No increase in fetal malformations was noted in pregnant rats receiving oral (gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation Days 6 to 15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased resorptions), fetotoxic (reduced fetal weights), and maternally toxic (reduced body weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the maximum human dose) was maternally lethal, and therefore, fetuses were not evaluated in this group. Also in this study, doses up to 50 mg/kg/day (8 times the maximum human dose) had no adverse effects on dams or fetuses. However, in the combined fertility, teratogenicity, and postnatal development study described above, 50 mg/kg clotrimazole was associated with reduced maternal weight gain and reduced numbers of offspring reared to 4 weeks. Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day (2-15 times the maximum human dose) were not teratogenic in mice. No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120, or 180 mg/kg/day (18-55 times the maximum human dose). Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. This dose is approximately one-fifth the maximum human dose. The abnormalities observed included umbilical hernias, cephalocele, and cleft palates. Betamethasone dipropionate has not been tested for teratogenic potential by the dermal route of administration. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals. 8.3 Nursing Mothers Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids can result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOTRISONE cream is administered to a nursing woman. 8.4 Pediatric Use The use of LOTRISONE cream in patients under 17 years of age is not recommended. Adverse events consistent with corticosteroid use have been observed in pediatric patients treated with LOTRISONE cream. In open-label trials, 17 of 43 (39.5%) evaluable pediatric subjects (aged 12-16 years old) using LOTRISONE cream for treatment of tinea pedis demonstrated adrenal suppression as determined by cosyntropin testing. In another open-label trial, 8 of 17 (47.1%) evaluable pediatric subjects (aged 12-16 years old) using LOTRISONE cream for treatment of tinea cruris demonstrated adrenal suppression as determined by cosyntropin testing. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression when they are treated with topical corticosteroids. They are, therefore also at greater risk of adrenal insufficiency during and/or after withdrawal of treatment. Pediatric patients may be more susceptible than adults to skin atrophy, including striae, when they are treated with topical corticosteroids. Reference ID: 3490830 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids [see Warnings and Precautions (5.1)]. Avoid use of LOTRISONE cream in the treatment of diaper dermatitis. 8.5 Geriatric Use Clinical studies of LOTRISONE cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, greater sensitivity of some older individuals cannot be ruled out. The use of LOTRISONE cream under occlusion, such as in diaper dermatitis, is not recommended. Postmarket adverse event reporting for LOTRISONE cream in patients aged 65 and above includes reports of skin atrophy and rare reports of skin ulceration. Caution should be exercised with the use of these corticosteroid-containing topical products on thinning skin. 11 DESCRIPTION LOTRISONE (clotrimazole and betamethasone dipropionate) cream, 1%/0.05%, contains combinations of clotrimazole, an azole antifungal, and betamethasone dipropionate, a corticosteroid, for topical use. Chemically, clotrimazole is 1–(o-chloro-α,α-diphenylbenzyl) imidazole, with the empirical formula C22H17CLN2, a molecular weight of 344.84, and the following structural formula: structural formula Clotrimazole is an odorless, white crystalline powder, insoluble in water and soluble in ethanol. Betamethasone dipropionate has 9-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21 structural formula Betamethasone dipropionate is a white to creamy-white, odorless crystalline powder, insoluble in water. Each gram of LOTRISONE cream contains 10 mg clotrimazole and 0.643 mg betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a white to off-white, hydrophilic cream consisting of benzyl alcohol as a preservative, ceteareth-30, cetyl alcohol plus stearyl alcohol, mineral oil, phosphoric acid, propylene glycol, purified water, sodium phosphate monobasic monohydrate, and white petrolatum. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Clotrimazole is an azole antifungal [see Clinical Pharmacology (12.4)]. Reference ID: 3490830 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Betamethasone dipropionate is a corticosteroid. Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action for the treatment of tinea pedis, tinea cruris and tinea corporis is unknown. 12.2 Pharmacodynamics Vasocontrictor Assay: Studies performed with LOTRISONE cream indicate that these topical combination antifungal/corticosteroids may have vasoconstrictor potencies in a range that is comparable to high-potency topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence. 12.3 Pharmacokinetics Skin penetration and systemic absorption of clotrimazole and betamethasone dipropionate following topical application of LOTRISONE cream has not been studied. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption of topical corticosteroids. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids [see Dosage and Administration (2)]. Once absorbed through the skin, the pharmacokinetics of topical corticosteroids are similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. 12.4 Microbiology Mechanism of Action: Clotrimazole, an azole antifungal agent, inhibits 14-α-demethylation of lanosterol in fungi by binding to one of the cytochrome P-450 enzymes. This leads to the accumulation of 14-α-methylsterols and reduced concentrations of ergosterol, a sterol essential for a normal fungal cytoplasmic membrane. The methylsterols may affect the electron transport system, thereby inhibiting growth of fungi. Activity In Vitro and In Vivo: Clotrimazole has been shown to be active against most strains of the following dermatophytes, both in vitro and in clinical infections, Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum [see Indications and Usage (1)]. Drug Resistance: Strains of dermatophytes having a natural resistance to clotrimazole have not been reported. Resistance to azoles, including clotrimazole, has been reported in some Candida species. No single-step or multiple-step resistance to clotrimazole has developed during successive passages of Trichophyton mentagrophytes. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There are no adequate laboratory animal studies with either the combination of clotrimazole and betamethasone dipropionate or with either component individually to evaluate carcinogenesis. Betamethasone was negative in the bacterial mutagenicity assay (Salmonella typhimurium and Escherichia coli) and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay. Reproductive studies with betamethasone dipropionate carried out in rabbits at doses of 1.0 mg/kg by the intramuscular route and in mice up to 33 mg/kg by the intramuscular route indicated no impairment of fertility except for dose-related increases in fetal resorption rates in both species. These doses are approximately 5- and 38-fold the maximum human dose based on body surface areas, respectively. In a combined study of the effects of clotrimazole on fertility, teratogenicity, and postnatal development, male and female rats were dosed orally (diet admixture) with levels of 5, 10, 25, or 50 mg/kg/day (approximately 1-8 times the maximum dose in a 60-kg adult based on body surface area) from 10 weeks prior to mating until 4 weeks postpartum. No adverse effects on the duration of estrous cycle, fertility, or duration of pregnancy were noted. 14 CLINICAL STUDIES In clinical trials of tinea corporis, tinea cruris, and tinea pedis, subjects treated with LOTRISONE cream showed a better clinical response at the first return visit than subjects treated with clotrimazole cream. In tinea corporis and tinea cruris, the subject returned 3 to 5 days after starting treatment, and in tinea pedis, after 1 week. Mycological cure rates observed in subjects treated with LOTRISONE cream were as good as, or better than, in those subjects treated with Reference ID: 3490830 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda clotrimazole cream. In these same clinical studies, patients treated with LOTRISONE cream showed better clinical responses and mycological cure rates when compared with subjects treated with betamethasone dipropionate cream. 16 HOW SUPPLIED/STORAGE AND HANDLING LOTRISONE cream is white to off-white and supplied in 15-gram (NDC 0085-0924-01) and 45-gram tubes (NDC 0085-0924-02), boxes of one. Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Rx only 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information) Inform the patient of the following: • Use LOTRISONE cream as directed by the physician. It is for external use only. • Avoid contact with the eyes, the mouth, or intravaginally. • Do not use LOTRISONE cream on the face or underarms. • Do not use more than 45 grams of LOTRISONE cream per week. • When using LOTRISONE cream in the groin area, patients should use the medication for 2 weeks only, and apply the cream sparingly. Patients should wear loose-fitting clothing. Notify the physician if the condition persists after 2 weeks. • Do not use LOTRISONE cream for any disorder other than that for which it was prescribed. • Do not bandage, cover or wrap the treatment area unless directed by the physician. Avoid use of LOTRISONE cream in the diaper area, as diapers or plastic pants may constitute occlusive dressing. • Report any signs of local adverse reactions to the physician. Advise patients that local reactions and skin atrophy are more likely to occur with occlusive use or prolonged use. • This medication is to be used for the full prescribed treatment time, even though the symptoms may have improved. Notify the physician if there is no improvement after 1 week of treatment for tinea cruris or tinea corporis, or after 2 weeks for tinea pedis. company logo Manufactured by: Schering Plough Canada Inc., Pointe Claire, Quebec H9R 1B4, Canada Copyright © 1983, 2013 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. For patent information: www.merck.com/product/patent/home.html Revised: 4/2014 uspi-mk5335A-cr-xxxxrxxx Reference ID: 3490830 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patient Information LOTRISONE® (LOW-tre-zone) (clotrimazole and betamethasone dipropionate) cream, 1%/0.05% Important information: LOTRISONE cream is for use on skin only. Do not use LOTRISONE cream in your eyes, mouth, or vagina. What is LOTRISONE cream? • LOTRISONE Cream is a prescription medication used on the skin (topical) to treat fungal infections of the feet, groin, and body in people 17 years of age and older. LOTRISONE Cream is used for fungal infections that are inflamed and have symptoms of redness or itching. • LOTRISONE cream should not be used in children under 17 years of age. Before using LOTRISONE cream, tell your healthcare provider about all your medical conditions, including if you: • are pregnant or plan to become pregnant. It is not known if LOTRISONE cream will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if LOTRISONE cream passes into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take other corticosteroid medicines by mouth or use other products on your skin or scalp that contain corticosteroids. What should I avoid while using LORTISONE cream? LORTISONE cream should not be used to treat diaper rash or redness. You should avoid applying LORTISONE cream in the diaper area. How should I use LOTRISONE cream? • Use LOTRISONE cream exactly as your healthcare provider tells you to use it. • Use LOTRISONE cream for the prescribed treatment time, even if your symptoms get better. • Do not use more than 45 grams of LOTRISONE cream in 1 week. • Do not bandage, cover, or wrap the treated area unless your healthcare provider tells you to. Wear loose-fitting clothing if you use LOTRISONE cream in the groin area. • Do not use LOTRISONE cream on your face or underarms (armpits). • For treatment of fungal infections of the groin and body: • Apply a thin layer of LOTRISONE cream to the affected skin area 2 times a day for 1 week. • Tell your healthcare provider if the treated skin area does not improve after 1 week of treatment. • Do not use LORTISONE cream for longer than 2 weeks. • For treatment of fungal infections of the feet: • Apply a thin layer of LOTRISONE cream to the affected skin area 2 times a day for 2 weeks. • Tell your healthcare provider if the treated skin area does not improve after 2 weeks of treatment. Do not use LOTRISONE cream longer than 4 weeks. • Wash your hands after applying LOTRISONE cream. What are the possible side effects of LOTRISONE cream? LOTRISONE cream may cause serious side effects, including: • LOTRISONE cream can pass through your skin. Too much LOTRISONE cream passing through your skin can cause your adrenal glands to stop working. Your healthcare provider may do blood tests to check for adrenal gland problems. The most common side effects of LOTRISONE cream include burning, tingling, rash, swelling, and infections. These are not all the possible side effects of LOTRISONE cream. 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 LOTRISONE cream ? • Store LOTRISONE cream at room temperature between 68°F to 77°F (20° C to 25°C). • Keep LOTRISONE cream and all medicines out of the reach of children. Reference ID: 3490830 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda General information about the safe and effective use of LOTRISONE cream. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about LOTRISONE cream that is written for health professionals. Do not use LOTRISONE cream for a condition for which it was not prescribed. Do not give LOTRISONE cream to other people, even if they have the same symptoms that you have. It may harm them. What are the ingredients in LOTRISONE cream? Active ingredients: clotrimazole and betamethasone dipropionate Inactive ingredients: benzyl alcohol as a preservative, ceteareth-30, cetyl alcohol plus stearyl alcohol, mineral oil, phosphoric acid, propylene glycol, purified water, sodium phosphate monobasic monohydrate, and white petrolatum Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA Manufactured by: Schering Plough Canada Inc., Pointe Claire, Quebec H9R 1B4, Canada Copyright © 1983, 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. For more information, go to www.merck.com/product/patent/home.html This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: April 2014 usppi-mk5335A-cr-XXXXrXXX Reference ID: 3490830 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:58.519379	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018827s046lbl.pdf', 'application_number': 18827, 'submission_type': 'SUPPL ', 'submission_number': 46}
11,344	LOTRISONE® Cream LOTRISONE® Lotion (clotrimazole and betamethasone dipropionate) FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. NOT RECOMMENDED FOR PATIENTS UNDER THE AGE OF 17 YEARS AND NOT RECOMMENDED FOR DIAPER DERMATITIS. DESCRIPTION LOTRISONE® Cream and Lotion contain combinations of clotrimazole, a synthetic antifungal agent, and betamethasone dipropionate, a synthetic corticosteroid, for dermatologic use. Chemically, clotrimazole is 1–(o-chloro-α,α-diphenylbenzyl) imidazole, with the empirical formula C H CIN 22 17 2, a molecular weight of 344.84, and the following structural formula: Clotrimazole is an odorless, white crystalline powder, insoluble in water and soluble in ethanol. Betamethasone dipropionate has the chemical name 9-fluoro-11β,17,21- trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, with the empirical formula C H FO 28 37 7, a molecular weight of 504.59, and the following structural formula: 1 LRN# 000370-LOS-MTL-USPI-1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 LRN# 000370-LOS-MTL-USPI-1 Betamethasone dipropionate is a white to creamy white, odorless crystalline powder, insoluble in water. Each gram of LOTRISONE Cream contains 10 mg clotrimazole and 0.643 mg betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a hydrophilic cream consisting of purified water, mineral oil, white petrolatum, cetyl alcohol plus stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate monobasic monohydrate, and phosphoric acid; benzyl alcohol as preservative. LOTRISONE Cream may contain sodium hydroxide. LOTRISONE Cream is smooth, uniform, and white to off-white in color. Each gram of LOTRISONE Lotion contains 10 mg clotrimazole and 0.643 mg betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a hydrophilic base of purified water, mineral oil, white petrolatum, cetyl alcohol plus stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate monobasic monohydrate, and phosphoric acid; benzyl alcohol as a preservative. LOTRISONE Lotion may contain sodium hydroxide. LOTRISONE Lotion is opaque and white in color. CLINICAL PHARMACOLOGY Clotrimazole and Betamethasone Dipropionate LOTRISONE® Cream has been shown to be at least as effective as clotrimazole alone in a different cream vehicle. No comparative studies have been conducted with LOTRISONE® Lotion and clotrimazole alone. Use of corticosteroids in the treatment of a fungal infection may lead to suppression of host inflammation leading to worsening or decreased cure rate. Clotrimazole Skin penetration and systemic absorption of clotrimazole following topical application of LOTRISONE Cream or Lotion have not been studied. The following information was obtained using 1% clotrimazole cream and solution formulations. Six hours after the application of radioactive clotrimazole 1% cream and 1% solution onto intact and acutely inflamed skin, the concentration of clotrimazole varied from 100 mcg/cm3 in the stratum corneum, to 0.5 to 1 mcg/cm3 in the reticular dermis, and 0.1 mcg/cm3 in the subcutis. No measurable amount of radioactivity (<0.001 mcg/mL) was found in the serum within 48 hours after application under occlusive dressing of 0.5 mL of the solution or 0.8 g of the cream. Only 0.5% or less of the applied radioactivity was excreted in the urine. Microbiology Mechanism of Action: Clotrimazole is an imidazole antifungal agent. Imidazoles inhibit 14-α-demethylation of lanosterol in fungi by binding to one of the cytochrome P-450 enzymes. This leads to the accumulation of 14-α- methylsterols and reduced concentrations of ergosterol, a sterol essential for a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 LRN# 000370-LOS-MTL-USPI-1 normal fungal cytoplasmic membrane. The methylsterols may affect the electron transport system, thereby inhibiting growth of fungi. Activity In Vivo: Clotrimazole has been shown to be active against most strains of the following dermatophytes, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section: Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum. Activity In Vitro: In vitro, clotrimazole has been shown to have activity against many dermatophytes, but the clinical significance of this information is unknown. Drug Resistance: Strains of dermatophytes having a natural resistance to clotrimazole have not been reported. Resistance to azoles including clotrimazole has been reported in some Candida species. No single-step or multiple-step resistance to clotrimazole has developed during successive passages of Trichophyton mentagrophytes. Betamethasone Dipropionate Betamethasone dipropionate, a corticosteroid, has been shown to have topical (dermatologic) and systemic pharmacologic and metabolic effects characteristic of this class of drugs. Pharmacokinetics The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier and the use of occlusive dressings (see DOSAGE AND ADMINISTRATION). Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption of topical corticosteroids. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids (see DOSAGE AND ADMINISTRATION). Once absorbed through the skin, the pharmacokinetics of topical corticosteroids are similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. Studies performed with LOTRISONE Cream and Lotion indicate that these topical combination antifungal/corticosteroids may have vasoconstrictor potencies in a range that is comparable to high potency topical corticosteroids. Therefore, use is not recommended in patients less than 17 years of age, in diaper dermatitis, and under occlusion. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 LRN# 000370-LOS-MTL-USPI-1 CLINICAL STUDIES (LOTRISONE® Cream) In clinical studies of tinea corporis, tinea cruris, and tinea pedis, patients treated with LOTRISONE Cream showed a better clinical response at the first return visit than patients treated with clotrimazole cream. In tinea corporis and tinea cruris, the patient returned 3 to 5 days after starting treatment, and in tinea pedis, after 1 week. Mycological cure rates observed in patients treated with LOTRISONE Cream were as good as or better than in those patients treated with clotrimazole cream. In these same clinical studies, patients treated with LOTRISONE Cream showed better clinical responses and mycological cure rates when compared with patients treated with betamethasone dipropionate cream. CLINICAL STUDIES (LOTRISONE® Lotion) In the treatment of tinea pedis twice daily for 4 weeks, LOTRISONE Lotion was shown to be superior to vehicle in relieving symptoms of erythema, scaling, pruritus, and maceration at week 2. LOTRISONE Lotion was also shown to have a superior mycological cure rate compared to vehicle 2 weeks after discontinuation of treatment. It is unclear if the relief of symptoms at 2 weeks in this clinical study with LOTRISONE Lotion was due to the contribution of betamethasone dipropionate, clotrimazole, or both. In the treatment of tinea cruris twice daily for 2 weeks, LOTRISONE Lotion was shown to be superior to vehicle in the relief of symptoms of erythema, scaling, and pruritus after 3 days. It is unclear if the relief of symptoms after 3 days in this clinical study with LOTRISONE Lotion was due to the contribution of betamethasone dipropionate, clotrimazole, or both. The comparative efficacy and safety of LOTRISONE Lotion versus clotrimazole alone in a lotion vehicle have not been studied in the treatment of tinea pedis or tinea cruris or tinea corporis. The comparative efficacy and safety of LOTRISONE Lotion and LOTRISONE Cream have also not been studied. INDICATIONS AND USAGE LOTRISONE® Cream and Lotion are indicated in patients 17 years and older for the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris, and tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum. Effective treatment without the risks associated with topical corticosteroid use may be obtained using a topical antifungal agent that does not contain a corticosteroid, especially for noninflammatory tinea infections. The efficacy of LOTRISONE Cream or Lotion for the treatment of infections caused by zoophilic dermatophytes (eg, Microsporum canis) has not been established. Several cases of treatment failure of LOTRISONE Cream in the treatment of infections caused by Microsporum canis have been reported. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 LRN# 000370-LOS-MTL-USPI-1 CONTRAINDICATIONS LOTRISONE® Cream or Lotion is contraindicated in patients who are sensitive to clotrimazole, betamethasone dipropionate, other corticosteroids or imidazoles, or to any ingredient in these preparations. PRECAUTIONS General Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Conditions which augment systemic absorption include use over large surface areas, prolonged use, and use under occlusive dressings. Use of more than one corticosteriod-containing product at the same time may increase total systemic glucocorticoid exposure. Patients applying LOTRISONE® Cream or Lotion to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, morning plasma cortisol, and urinary-free cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. In a small study, LOTRISONE Cream was applied using large dosages, 7 g daily for 14 days (BID) to the crural area of normal adult subjects. Three of the eight normal subjects on whom LOTRISONE Cream was applied exhibited low morning plasma cortisol levels during treatment. One of these subjects had an abnormal Cortrosyn test. The effect on morning plasma cortisol was transient and subjects recovered one week after discontinuing dosing. In addition, two separate studies in pediatric patients demonstrated adrenal suppression as determined by cosyntropin testing (see PRECAUTIONS, Pediatric Use section). Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONS, Pediatric Use section). If irritation develops, LOTRISONE Cream or Lotion should be discontinued and appropriate therapy instituted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 LRN# 000370-LOS-MTL-USPI-1 THE SAFETY OF LOTRISONE CREAM OR LOTION HAS NOT BEEN DEMONSTRATED IN THE TREATMENT OF DIAPER DERMATITIS. ADVERSE EVENTS CONSISTENT WITH CORTICOSTEROID USE HAVE BEEN OBSERVED IN PATIENTS TREATED WITH LOTRISONE CREAM FOR DIAPER DERMATITIS. THE USE OF LOTRISONE CREAM OR LOTION IN THE TREATMENT OF DIAPER DERMATITIS IS NOT RECOMMENDED. Information for Patients Patients using LOTRISONE Cream or Lotion should receive the following information and instructions: 1. The medication is to be used as directed by the physician and is not recommended for use longer than the prescribed time period. It is for external use only. Avoid contact with the eyes, the mouth, or intravaginally. 2. This medication is to be used for the full prescribed treatment time, even though the symptoms may have improved. Notify the physician if there is no improvement after 1 week of treatment for tinea cruris or tinea corporis, or after 2 weeks for tinea pedis. 3. This medication should only be used for the disorder for which it was prescribed. 4. Other corticosteroid-containing products should not be used with LOTRISONE without first talking with your physician. 5. The treated skin area should not be bandaged, covered, or wrapped so as to be occluded (see DOSAGE AND ADMINISTRATION). 6. Any signs of local adverse reactions should be reported to your physician. 7. Patients should avoid sources of infection or reinfection. 8. When using LOTRISONE Cream or Lotion in the groin area, patients should use the medication for 2 weeks only, and apply the cream or lotion sparingly. Patients should wear loose-fitting clothing. Notify the physician if the condition persists after 2 weeks. 9. The safety of LOTRISONE Cream or Lotion has not been demonstrated in the treatment of diaper dermatitis. Adverse events consistent with corticosteroid use have been observed in patients treated with LOTRISONE Cream for diaper dermatitis. The use of LOTRISONE Cream or Lotion in the treatment of diaper dermatitis is not recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 LRN# 000370-LOS-MTL-USPI-1 Laboratory Tests If there is a lack of response to LOTRISONE Cream or Lotion, appropriate confirmation of the diagnosis, including possible mycological studies, is indicated before instituting another course of therapy. The following tests may be helpful in evaluating HPA-axis suppression due to the corticosteroid components: Urinary-free cortisol test Morning plasma cortisol test ACTH (cosyntropin) stimulation test Carcinogenesis, Mutagenesis, Impairment of Fertility There are no adequate laboratory animal studies with either the combination of clotrimazole and betamethasone dipropionate or with either component individually to evaluate carcinogenesis. Betamethasone was negative in the bacterial mutagenicity assay (Salmonella typhimurium and Escherichia coli) and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay. This pattern of response is similar to that of dexamethasone and hydrocortisone. Reproductive studies with betamethasone dipropionate carried out in rabbits at doses of 1.0 mg/kg by the intramuscular route and in mice up to 33 mg/kg by the intramuscular route indicated no impairment of fertility except for dose-related increases in fetal resorption rates in both species. These doses are approximately 5- and 38-fold the maximum human dose based on body surface areas, respectively. In a combined study of the effects of clotrimazole on fertility, teratogenicity, and postnatal development, male and female rats were dosed orally (diet admixture) with levels of 5, 10, 25, or 50 mg/kg/day (approximately 1-8 times the maximum dose in a 60 kg adult based on body surface area) from 10 weeks prior to mating until 4 weeks postpartum. No adverse effects on the duration of estrous cycle, fertility, or duration of pregnancy were noted. Pregnancy Teratogenic Effects Pregnancy Category C There have been no teratogenic studies performed in animals or humans with the combination of clotrimazole and betamethasone dipropionate. Corticosteroids are generally teratogenic in laboratory animals when administered at relatively low dosage levels. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 LRN# 000370-LOS-MTL-USPI-1 Studies in pregnant rats with intravaginal doses up to 100 mg/kg (15 times the maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole exposure. No increase in fetal malformations was noted in pregnant rats receiving oral (gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation days 6- 15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased resorptions), fetotoxic (reduced fetal weights) and maternally toxic (reduced body weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the maximum human dose) was maternally lethal, and therefore fetuses were not evaluated in this group. Also in this study, doses up to 50 mg/kg/day (8 times the maximum human dose) had no adverse effects on dams or fetuses. However, in the combined fertility, teratogenicity, and postnatal development study described above, 50 mg/kg clotrimazole, was associated with reduced maternal weight gain and reduced numbers of offspring reared to 4 weeks. Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day (2-15 times the maximum human dose) were not teratogenic in mice. No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120, or 180 mg/kg/day (18-55 times the maximum human dose). Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. This dose is approximately one-fifth the maximum human dose. The abnormalities observed included umbilical hernias, cephalocele and cleft palates. Betamethasone dipropionate has not been tested for teratogenic potential by the dermal route of administration. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals. There are no adequate and well-controlled studies in pregnant women of the teratogenic effects of topically applied corticosteroids. Therefore, LOTRISONE Cream or Lotion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOTRISONE Cream or Lotion is administered to a nursing woman. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 LRN# 000370-LOS-MTL-USPI-1 Pediatric Use Adverse events consistent with corticosteroid use have been observed in patients under 12 years of age treated with LOTRISONE Cream. In open-label studies, 17 of 43 (39.5%) evaluable pediatric patients (aged 12 to 16 years old) using LOTRISONE Cream for treatment of tinea pedis demonstrated adrenal suppression as determined by cosyntropin testing. In another open-label study, 8 of 17 (47.1%) evaluable pediatric patients (aged 12 to 16 years old) using LOTRISONE Cream for treatment of tinea cruris demonstrated adrenal suppression as determined by cosyntropin testing. THE USE OF LOTRISONE CREAM OR LOTION IN THE TREATMENT OF PATIENTS UNDER 17 YEARS OF AGE OR PATIENTS WITH DIAPER DERMATITIS IS NOT RECOMMENDED. Because of higher ratio of skin surface area to body mass, pediatric patients under the age of 12 years are at a higher risk with LOTRISONE Cream or Lotion. The studies described above suggest that pediatric patients under the age of 17 years may also have this risk. They are at increased risk of developing Cushing’s syndrome while on treatment and adrenal insufficiency after withdrawal of treatment. Adverse effects, including striae and growth retardation, have been reported with inappropriate use of LOTRISONE Cream in infants and children (see PRECAUTIONS and ADVERSE REACTIONS). Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Geriatric Use Clinical studies of LOTRISONE Cream and Lotion did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Postmarket adverse event reporting for LOTRISONE Cream in patients aged 65 and above includes reports of skin atrophy and rare reports of skin ulceration. Caution should be exercised with the use of these corticosteroid-containing topical products on thinning skin. THE USE OF LOTRISONE CREAM OR LOTION UNDER OCCLUSION, SUCH AS IN DIAPER DERMATITIS, IS NOT RECOMMENDED. ADVERSE REACTIONS Adverse reactions reported for LOTRISONE® Cream in clinical trials were paresthesia in 1.9% of patients, and rash, edema, and secondary infection, each in less than 1% of patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 LRN# 000370-LOS-MTL-USPI-1 Adverse reactions reported for LOTRISONE® Lotion in clinical trials were burning and dry skin in 1.6% of patients and stinging in less than 1% of patients. The following local adverse reactions have been reported with topical corticosteroids and may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, miliaria, capillary fragility (ecchymoses), and sensitization (local reactions upon repeated application of product). In the pediatric population, reported adverse events for LOTRISONE Cream include growth retardation, benign intracranial hypertension, Cushing’s syndrome (HPA axis suppression), and local cutaneous reactions, including skin atrophy. Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Adverse reactions reported with the use of clotrimazole are as follows: erythema, stinging, blistering, peeling, edema, pruritus, urticaria, and general irritation of the skin. OVERDOSAGE Amounts greater than 45 g/week of LOTRISONE® Cream or 45 mL/week of LOTRISONE® Lotion should not be used. Acute overdosage with topical application of LOTRISONE Cream or Lotion is unlikely and would not be expected to lead to a life-threatening situation. LOTRISONE Cream or Lotion should not be used for longer than the prescribed time period. Topically applied corticosteroids, such as the one contained in LOTRISONE Cream or Lotion can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS). DOSAGE AND ADMINISTRATION Gently massage sufficient LOTRISONE® Cream or Lotion into the affected skin areas twice a day, in the morning and evening. LOTRISONE Cream or Lotion should not be used longer than 2 weeks in the treatment of tinea corporis or tinea cruris, and amounts greater than 45 g per week of LOTRISONE Cream or amounts greater than 45 mL per week of LOTRISONE Lotion should not be used. If a patient with tinea corporis or tinea cruris shows no clinical improvement after 1 week of treatment with LOTRISONE Cream or Lotion, the diagnosis should be reviewed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 LRN# 000370-LOS-MTL-USPI-1 LOTRISONE Cream or Lotion should not be used longer than 4 weeks in the treatment of tinea pedis and amounts greater than 45 g per week of LOTRISONE Cream or amounts greater than 45 mL per week of LOTRISONE Lotion should not be used. If a patient with tinea pedis shows no clinical improvement after 2 weeks of treatment with LOTRISONE Cream or Lotion, the diagnosis should be reviewed. LOTRISONE Cream or Lotion should not be used with occlusive dressings. HOW SUPPLIED LOTRISONE® Cream is supplied in 15-g (NDC 0085-0924-01) and 45-g tubes (NDC 0085-0924-02); boxes of one. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. LOTRISONE® Lotion is supplied in 30-mL bottles (NDC 0085-0809-01), box of one. Store at 25°C (77°F) in the upright position only; excursions permitted between 15°C and 30°C (59°F and 86°F). SHAKE LOTION WELL BEFORE EACH USE. Rx only Schering Corporation Kenilworth, NJ 07033 USA Rev. 01/08 Copyright © 2000, 2007, Schering 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 1 LRN# 000370-LOS-MTL-PPI-1 LOTRISONE® Cream LOTRISONE® Lotion (clotrimazole and betamethasone dipropionate) Patient’s Instructions for Use SHAKE LOTION WELL BEFORE EACH USE Patient Information Leaflet What is LOTRISONE® Cream or Lotion? LOTRISONE Cream and Lotion are medications used on the skin to treat fungal infections of the feet, groin and body, as diagnosed by your doctor. LOTRISONE Cream or Lotion should be used for fungal infections that are inflamed and have symptoms of redness and/or itching. Talk to your doctor if your fungal infection does not have these symptoms. LOTRISONE Cream and Lotion contain a corticosteroid. Notify your doctor if you notice side effects with the use of LOTRISONE Cream or Lotion (see “What are the possible side effects of LOTRISONE Cream and Lotion?” below). LOTRISONE Cream or Lotion is not to be used in the eyes, in the mouth, or in the vagina. How do LOTRISONE® Cream and Lotion work? LOTRISONE Cream and Lotion are combinations of an antifungal agent (clotrimazole) and a corticosteroid (betamethasone dipropionate). Clotrimazole works against fungus. Betamethasone dipropionate, a corticosteroid, is used to help relieve redness, swelling, itching, and other discomforts of fungal infections. Who should NOT use LOTRISONE® Cream or Lotion? LOTRISONE Cream and Lotion are not recommended for use in patients under the age of 17 years. LOTRISONE Cream or Lotion is not recommended for use in diaper rash. Patients who are sensitive to clotrimazole and betamethasone dipropionate, other corticosteroids or imidazoles, or any ingredients in the preparation should not use LOTRISONE Cream and Lotion. How should I use LOTRISONE® Cream or Lotion? Gently massage sufficient LOTRISONE Cream or Lotion into the affected and surrounding skin areas twice a day, in the morning and evening. Treatment for 2 weeks on the groin or on the body, and for 4 weeks on the feet is recommended. The use of LOTRISONE Cream or Lotion for longer than 4 weeks is not This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 LRN# 000370-LOS-MTL-PPI-1 recommended for any condition. Prolonged use of LOTRISONE Cream or Lotion may lead to unwanted side effects. What other important information should I know about LOTRISONE® Cream and Lotion? 1. This medication is to be used for the full prescribed treatment time, even though the symptoms may have improved. Notify your doctor if there is no improvement after 1 week of treatment on the groin or body or after 2 weeks on the feet. 2. This medication should only be used for the disorder for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped. 4. Other corticosteroid-containing products should not be used with LOTRISONE without first talking with your physician. 5. Any signs of side effects where LOTRISONE Cream or Lotion is applied should be reported to your doctor. 6. When using LOTRISONE Cream or Lotion in the groin area, it is especially important to use the medication for 2 weeks only, and to apply the cream or lotion sparingly. You should tell your doctor if your problem persists after 2 weeks. You should also wear loose-fitting clothing so as to avoid tightly covering the area where LOTRISONE Cream or Lotion is applied. 7. This medication is not recommended for use in diaper rash. What are the possible side effects of LOTRISONE® Cream and Lotion? The following side effects have been reported with topical corticosteroid medications: itching, irritation, dryness, infection of the hair follicles, increased hair, acne, fragile blood vessels, sensitization (local reactions upon repeated application of product), change in skin color, allergic skin reaction, skin thinning, and stretch marks. In children, reported adverse events for LOTRISONE Cream include slower growth, Cushing’s syndrome (a type of hormone imbalance that can be very serious), and local skin reactions, including thinning skin and stretch marks. Hormone imbalance (adrenal suppression) was demonstrated in clinical studies in children. Can LOTRISONE® Cream or Lotion be used if I am pregnant or plan to become pregnant or if I am nursing? Before using LOTRISONE Cream or Lotion, tell your doctor if you are pregnant or plan to become pregnant. Also, tell your doctor if you are nursing. How should LOTRISONE® Cream or Lotion be stored? LOTRISONE Cream should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 LRN# 000370-LOS-MTL-PPI-1 LOTRISONE Lotion should be stored at 25°C (77°F) in the upright position only; excursions permitted between 15°C and 30°C (59°F and 86°F). Shake well before using LOTRISONE Lotion. General advice about prescription medicines This medicine was prescribed for your particular condition. Only use LOTRISONE® Cream or Lotion to treat the condition for which your doctor has prescribed. Do not give LOTRISONE Cream or Lotion to other people. It may harm them. This leaflet summarizes the most important information about LOTRISONE Cream and Lotion. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about LOTRISONE Cream and Lotion that is written for health professionals. Rx only Schering Corporation Kenilworth, NJ 07033 USA Copyright © 2000, 2007, Schering Corporation. All rights reserved. Rev.01/08 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:58.585849	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018827s038lbl.pdf', 'application_number': 18827, 'submission_type': 'SUPPL ', 'submission_number': 38}
11,349	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). 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 mOsmol/L. Administration of substantially hypertonic solutions (≥600 mOsmol/L) may cause vein damage. 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 animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 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) produce 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. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in VIAFLEX Plastic Container 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 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. 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 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. 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. 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. 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. 07-19-44-383 O OH • H2O OH OH HO CH2OH D-Glucopyranose monohydrate 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 07-19-44-383 Rev. July 2004 Baxter, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 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. 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 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 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 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. 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. 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. Do not administer unless solution is clear and the 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. 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. 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 VIAFLEX plastic containers is available as shown below: Code Size (mL) NDC 2B2112 250 NDC 0338-0141-02 2B2113 500 NDC 0338-0141-03 2B2114 1000 NDC 0338-0141-04 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 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. 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. *BAR CODE POSITION ONLY 071944383 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:58.789722	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018840s028lbl.pdf', 'application_number': 18840, 'submission_type': 'SUPPL ', 'submission_number': 28}
11,348	1 PRESCRIBING INFORMATION ZOVIRAX® (acyclovir) Capsules ZOVIRAX® (acyclovir) Tablets ZOVIRAX® (acyclovir) Suspension DESCRIPTION ZOVIRAX is the brand name for acyclovir, a synthetic nucleoside analogue active against herpesviruses. ZOVIRAX Capsules, Tablets, and Suspension are formulations for oral administration. Each capsule of ZOVIRAX contains 200 mg of acyclovir and the inactive ingredients corn starch, lactose, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C Blue No. 2, and titanium dioxide. May contain one or more parabens. Printed with edible black ink. Each 800-mg tablet of ZOVIRAX contains 800 mg of acyclovir and the inactive ingredients FD&C Blue No. 2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Each 400-mg tablet of ZOVIRAX contains 400 mg of acyclovir and the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Each teaspoonful (5 mL) of ZOVIRAX Suspension contains 200 mg of acyclovir and the inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as preservatives), carboxymethylcellulose sodium, flavor, glycerin, microcrystalline cellulose, and sorbitol. Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka’s of acyclovir are 2.27 and 9.25. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H- purin-6-one; it has the following structural formula: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 VIROLOGY Mechanism of Antiviral Action: Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK. Antiviral Activities: The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL. Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy. CLINICAL PHARMACOLOGY Pharmacokinetics: The pharmacokinetics of acyclovir after oral administration have been evaluated in healthy volunteers and in immunocompromised patients with herpes simplex or varicella-zoster virus infection. Acyclovir pharmacokinetic parameters are summarized in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Table 1. Acyclovir Pharmacokinetic Characteristics (Range) Parameter Range Plasma protein binding 9% to 33% Plasma elimination half-life 2.5 to 3.3 hr Average oral bioavailability 10% to 20%* *Bioavailability decreases with increasing dose. In one multiple-dose, crossover study in healthy subjects (n = 23), it was shown that increases in plasma acyclovir concentrations were less than dose proportional with increasing dose, as shown in Table 2. The decrease in bioavailability is a function of the dose and not the dosage form. Table 2. Acyclovir Peak and Trough Concentrations at Steady State Parameter 200 mg 400 mg 800 mg max SS C 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL trough SS C 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL There was no effect of food on the absorption of acyclovir (n = 6); therefore, ZOVIRAX Capsules, Tablets, and Suspension may be administered with or without food. The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine. Special Populations: Adults With Impaired Renal Function: The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION). Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use). Pediatrics: In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300 mg/m2 and 600 mg/m2 in pediatric patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours). Drug Interactions: Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced. Clinical Trials: Initial Genital Herpes: Double-blind, placebo-controlled studies have demonstrated that orally administered ZOVIRAX significantly reduced the duration of acute infection and duration of lesion healing. The duration of pain and new lesion formation was decreased in some patient groups. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Recurrent Genital Herpes: Double-blind, placebo-controlled studies in patients with frequent recurrences (6 or more episodes per year) have shown that orally administered ZOVIRAX given daily for 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients. In a study of patients who received ZOVIRAX 400 mg twice daily for 3 years, 45%, 52%, and 63% of patients remained free of recurrences in the first, second, and third years, respectively. Serial analyses of the 3-month recurrence rates for the patients showed that 71% to 87% were recurrence free in each quarter. Herpes Zoster Infections: In a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, ZOVIRAX (800 mg 5 times daily for 10 days) shortened the times to lesion scabbing, healing, and complete cessation of pain, and reduced the duration of viral shedding and the duration of new lesion formation. In a similar double-blind, placebo-controlled study, ZOVIRAX (800 mg 5 times daily for 7 days) shortened the times to complete lesion scabbing, healing, and cessation of pain; reduced the duration of new lesion formation; and reduced the prevalence of localized zoster-associated neurologic symptoms (paresthesia, dysesthesia, or hyperesthesia). Treatment was begun within 72 hours of rash onset and was most effective if started within the first 48 hours. Adults greater than 50 years of age showed greater benefit. Chickenpox: Three randomized, double-blind, placebo-controlled trials were conducted in 993 pediatric patients aged 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In 2 trials, ZOVIRAX was administered at 20 mg/kg 4 times daily (up to 3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4 times daily for 5 to 7 days. Treatment with ZOVIRAX shortened the time to 50% healing; reduced the maximum number of lesions; reduced the median number of vesicles; decreased the median number of residual lesions on day 28; and decreased the proportion of patients with fever, anorexia, and lethargy by day 2. Treatment with ZOVIRAX did not affect varicella-zoster virus-specific humoral or cellular immune responses at 1 month or 1 year following treatment. INDICATIONS AND USAGE Herpes Zoster Infections: ZOVIRAX is indicated for the acute treatment of herpes zoster (shingles). Genital Herpes: ZOVIRAX is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes. Chickenpox: ZOVIRAX is indicated for the treatment of chickenpox (varicella). CONTRAINDICATIONS ZOVIRAX is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 WARNINGS ZOVIRAX Capsules, Tablets, and Suspension are intended for oral ingestion only. Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS: Observed During Clinical Practice and OVERDOSAGE). Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy. PRECAUTIONS Dosage adjustment is recommended when administering ZOVIRAX to patients with renal impairment (see DOSAGE AND ADMINISTRATION). Caution should also be exercised when administering ZOVIRAX to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as those that have been reported in patients treated with intravenous acyclovir. Adequate hydration should be maintained. Information for Patients: Patients are instructed to consult with their physician if they experience severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they intend to breastfeed while taking orally administered ZOVIRAX, or they have any other questions. Patients should be advised to maintain adequate hydration. Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster. Genital Herpes Infections: Patients should be informed that ZOVIRAX is not a cure for genital herpes. There are no data evaluating whether ZOVIRAX will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode. Chickenpox: Chickenpox in otherwise healthy children is usually a self-limited disease of mild to moderate severity. Adolescents and adults tend to have more severe disease. Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the disease course. Drug Interactions: See CLINICAL PHARMACOLOGY: Pharmacokinetics. Carcinogenesis, Mutagenesis, Impairment of Fertility: The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors. Maximum plasma concentrations were 3 to 6 times human levels in the mouse bioassay and 1 to 2 times human levels in the rat bioassay. Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positive in 5 of the assays. Acyclovir did not impair fertility or reproduction in mice (450 mg/kg/day, p.o.) or in rats (25 mg/kg/day, s.c.). In the mouse study, plasma levels were 9 to 18 times human levels, while in the rat study, they were 8 to 15 times human levels. At higher doses (50 mg/kg/day, s.c.) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg/day, s.c., there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses. No testicular abnormalities were seen in dogs given 50 mg/kg/day, IV for 1 month (21 to 41 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (6 to 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels. Pregnancy: Teratogenic Effects: Pregnancy Category B. Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day, s.c. and IV), or rat (50 mg/kg/day, s.c.). These exposures resulted in plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels. There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of ZOVIRAX and ranged from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day. ZOVIRAX should be administered to a nursing mother with caution and only when indicated. Pediatric Use: Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Geriatric Use: Of 376 subjects who received ZOVIRAX in a clinical study of herpes zoster treatment in immunocompetent subjects ≥50 years of age, 244 were 65 and over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adult subjects. The duration of pain after healing was longer in patients 65 and over. Nausea, vomiting, and dizziness were reported more frequently in elderly subjects. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Herpes Simplex: Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with ZOVIRAX 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo. Long-Term Administration: The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules) 2 times daily for 1 year in 586 patients treated with ZOVIRAX were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with ZOVIRAX for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%). Herpes Zoster: The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral ZOVIRAX 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%). Chickenpox: The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral ZOVIRAX at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%). Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of ZOVIRAX. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to ZOVIRAX, or a combination of these factors. General: Anaphylaxis, angioedema, fever, headache, pain, peripheral edema. Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment (see PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Digestive: Diarrhea, gastrointestinal distress, nausea. Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia. Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice. Musculoskeletal: Myalgia. Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria. Special Senses: Visual abnormalities. Urogenital: Renal failure, renal pain (may be associated with renal failure), elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS). OVERDOSAGE Overdoses involving ingestion of up to 100 capsules (20 g) have been reported. Adverse events that have been reported in association with overdosage include agitation, coma, seizures, and lethargy. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Overdosage has been reported following bolus injections or inappropriately high doses and in patients whose fluid and electrolyte balance were not properly monitored. This has resulted in elevated BUN and serum creatinine and subsequent renal failure. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION). DOSAGE AND ADMINISTRATION Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days. Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease: 400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily. The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re-evaluated to assess the need for continuation of therapy with ZOVIRAX. Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence. Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox. Adults and Children over 40 kg: 800 mg 4 times daily for 5 days. Intravenous ZOVIRAX is indicated for the treatment of varicella-zoster infections in immunocompromised patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms. Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose of ZOVIRAX Capsules, Tablets, or Suspension should be modified as shown in Table 3: Table 3. Dosage Modification for Renal Impairment Normal Dosage Regimen Creatinine Clearance (mL/min/1.73 m2) Adjusted Dosage Regimen Dose (mg) Dosing Interval 200 mg every 4 hours >10 200 every 4 hours, 5x daily 0-10 200 every 12 hours 400 mg every 12 hours >10 400 every 12 hours 0-10 200 every 12 hours 800 mg every 4 hours >25 800 every 4 hours, 5x daily 10-25 800 every 8 hours 0-10 800 every 12 hours Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis. Peritoneal Dialysis: No supplemental dose appears to be necessary after adjustment of the dosing interval. Bioequivalence of Dosage Forms: ZOVIRAX Suspension was shown to be bioequivalent to ZOVIRAX Capsules (n = 20) and 1 ZOVIRAX 800-mg tablet was shown to be bioequivalent to 4 ZOVIRAX 200-mg capsules (n = 24). HOW SUPPLIED ZOVIRAX Capsules (blue, opaque cap and body) containing 200 mg acyclovir and printed with “Wellcome ZOVIRAX 200.” Bottle of 100 (NDC 0173-0991-55). Unit dose pack of 100 (NDC 0173-0991-56). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Tablets (light blue, oval) containing 800 mg acyclovir and engraved with “ZOVIRAX 800.” Bottle of 100 (NDC 0173-0945-55). Store at 15° to 25°C (59° to 77°F) and protect from moisture. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 ZOVIRAX Tablets (white, shield-shaped) containing 400 mg acyclovir and engraved with "ZOVIRAX" on one side and a triangle on the other side. Bottle of 100 (NDC 0173-0949-55). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Suspension (off-white, banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL). Bottle of 1 pint (473 mL) (NDC 0173-0953-96). Store at 15° to 25°C (59° to 77°F). ZOVIRAX is a registered trademark of GlaxoSmithKline. GlaxoSmithKline Research Triangle Park, NC 27709 2007, GlaxoSmithKline. All rights reserved. October 2007 ZVT:1PI This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:59.024942	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018828s031lbl.pdf', 'application_number': 18828, 'submission_type': 'SUPPL ', 'submission_number': 31}
11,347	NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 3 PRESCRIBING INFORMATION ZOVIRAX® (acyclovir) Capsules ZOVIRAX® (acyclovir) Tablets ZOVIRAX® (acyclovir) Suspension DESCRIPTION ZOVIRAX is the brand name for acyclovir, a synthetic nucleoside analogue active against herpesviruses. ZOVIRAX Capsules, Tablets, and Suspension are formulations for oral administration. Each capsule of ZOVIRAX contains 200 mg of acyclovir and the inactive ingredients corn starch, lactose, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C Blue No. 2, and titanium dioxide. May contain one or more parabens. Printed with edible black ink. Each 800-mg tablet of ZOVIRAX contains 800 mg of acyclovir and the inactive ingredients FD&C Blue No. 2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Each 400-mg tablet of ZOVIRAX contains 400 mg of acyclovir and the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Each teaspoonful (5 mL) of ZOVIRAX Suspension contains 200 mg of acyclovir and the inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as preservatives), carboxymethylcellulose sodium, flavor, glycerin, microcrystalline cellulose, and sorbitol. Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka’s of acyclovir are 2.27 and 9.25. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6- one; it has the following structural formula: VIROLOGY This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 4 Mechanism of Antiviral Action: Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK. Antiviral Activities: The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL. Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy. CLINICAL PHARMACOLOGY Pharmacokinetics: The pharmacokinetics of acyclovir after oral administration have been evaluated in healthy volunteers and in immunocompromised patients with herpes simplex or varicella-zoster virus infection. Acyclovir pharmacokinetic parameters are summarized in Table 1. Table 1. Acyclovir Pharmacokinetic Characteristics (Range) Parameter Range Plasma protein binding 9% to 33% Plasma elimination half-life 2.5 to 3.3 hr Average oral bioavailability 10% to 20%* *Bioavailability decreases with increasing dose. In one multiple-dose, crossover study in healthy subjects (n = 23), it was shown that increases in plasma acyclovir concentrations were less than dose proportional with increasing dose, as shown in Table 2. The decrease in bioavailability is a function of the dose and not the dosage form. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 5 Table 2. Acyclovir Peak and Trough Concentrations at Steady State Parameter 200 mg 400 mg 800 mg max SS C 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL trough SS C 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL There was no effect of food on the absorption of acyclovir (n = 6); therefore, ZOVIRAX Capsules, Tablets, and Suspension may be administered with or without food. The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine. Special Populations: Adults with Impaired Renal Function: The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION). Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use). Pediatrics: In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300 mg/m2 and 600 mg/m2 in pediatric patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours). Drug Interactions: Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced. Clinical Trials: Initial Genital Herpes: Double-blind, placebo-controlled studies have demonstrated that orally administered ZOVIRAX significantly reduced the duration of acute infection and duration of lesion healing. The duration of pain and new lesion formation was decreased in some patient groups. Recurrent Genital Herpes: Double-blind, placebo-controlled studies in patients with frequent recurrences (6 or more episodes per year) have shown that orally administered ZOVIRAX given daily for 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients. In a study of patients who received ZOVIRAX 400 mg twice daily for 3 years, 45%, 52%, and 63% of patients remained free of recurrences in the first, second, and third years, respectively. Serial analyses of the 3-month recurrence rates for the patients showed that 71% to 87% were recurrence free in each quarter. Herpes Zoster Infections: In a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, ZOVIRAX (800 mg 5 times daily for 10 days) shortened the times to lesion scabbing, healing, and complete cessation of pain, and reduced the duration of viral shedding and the duration of new lesion formation. In a similar double-blind, placebo-controlled study, ZOVIRAX (800 mg 5 times daily for 7 days) shortened the times to complete lesion scabbing, healing, and cessation of pain; reduced the duration of new lesion formation; and reduced the prevalence of localized zoster-associated neurologic symptoms (paresthesia, dysesthesia, or hyperesthesia). Treatment was begun within 72 hours of rash onset and was most effective if started within the first 48 hours. Adults greater than 50 years of age showed greater benefit. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 6 Chickenpox: Three randomized, double-blind, placebo-controlled trials were conducted in 993 pediatric patients aged 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In 2 trials, ZOVIRAX was administered at 20 mg/kg 4 times daily (up to 3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4 times daily for 5 to 7 days. Treatment with ZOVIRAX shortened the time to 50% healing; reduced the maximum number of lesions; reduced the median number of vesicles; decreased the median number of residual lesions on day 28; and decreased the proportion of patients with fever, anorexia, and lethargy by day 2. Treatment with ZOVIRAX did not affect varicella-zoster virus-specific humoral or cellular immune responses at 1 month or 1 year following treatment. INDICATIONS AND USAGE Herpes Zoster Infections: ZOVIRAX is indicated for the acute treatment of herpes zoster (shingles). Genital Herpes: ZOVIRAX is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes. Chickenpox: ZOVIRAX is indicated for the treatment of chickenpox (varicella). CONTRAINDICATIONS ZOVIRAX is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir. WARNINGS ZOVIRAX Capsules, Tablets, and Suspension are intended for oral ingestion only. Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS: Observed During Clinical Practice and OVERDOSAGE). Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy. PRECAUTIONS Dosage adjustment is recommended when administering ZOVIRAX to patients with renal impairment (see DOSAGE AND ADMINISTRATION). Caution should also be exercised when administering ZOVIRAX to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as those that have been reported in patients treated with intravenous acyclovir. Information for Patients: Patients are instructed to consult with their physician if they experience severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they intend to breastfeed while taking orally administered ZOVIRAX, or they have any other questions. Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster. Genital Herpes Infections: Patients should be informed that ZOVIRAX is not a cure for genital herpes. There are no data evaluating whether ZOVIRAX will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 7 Chickenpox: Chickenpox in otherwise healthy children is usually a self-limited disease of mild to moderate severity. Adolescents and adults tend to have more severe disease. Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the disease course. Drug Interactions: See CLINICAL PHARMACOLOGY: Pharmacokinetics. Carcinogenesis, Mutagenesis, Impairment of Fertility: The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors. Maximum plasma concentrations were 3 to 6 times human levels in the mouse bioassay and 1 to 2 times human levels in the rat bioassay. Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positive in 5 of the assays. Acyclovir did not impair fertility or reproduction in mice (450 mg/kg/day, p.o.) or in rats (25 mg/kg/day, s.c.). In the mouse study, plasma levels were 9 to 18 times human levels, while in the rat study, they were 8 to 15 times human levels. At higher doses (50 mg/kg/day, s.c.) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg/day, s.c., there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses. No testicular abnormalities were seen in dogs given 50 mg/kg/day, IV for 1 month (21 to 41 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (6 to 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels. Pregnancy: Teratogenic Effects: Pregnancy Category B. Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day, s.c. and IV), or rat (50 mg/kg/day, s.c.). These exposures resulted in plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels. There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of ZOVIRAX and ranged from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day. ZOVIRAX should be administered to a nursing mother with caution and only when indicated. Pediatric Use: Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 8 Geriatric Use: Of 376 subjects who received ZOVIRAX in a clinical study of herpes zoster treatment in immunocompetent subjects ≥50 years of age, 244 were 65 and over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adult subjects. The duration of pain after healing was longer in patients 65 and over. Nausea, vomiting, and dizziness were reported more frequently in elderly subjects. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Herpes Simplex: Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with ZOVIRAX 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo. Long-Term Administration: The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules) 2 times daily for 1 year in 586 patients treated with ZOVIRAX were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with ZOVIRAX for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%). Herpes Zoster: The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral ZOVIRAX 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%). Chickenpox: The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral ZOVIRAX at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%). Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of ZOVIRAX. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to ZOVIRAX, or a combination of these factors. General: Anaphylaxis, angioedema, fever, headache, pain, peripheral edema. Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment (see PRECAUTIONS). Digestive: Diarrhea, gastrointestinal distress, nausea. Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia. Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice. Musculoskeletal: Myalgia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 9 Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria. Special Senses: Visual abnormalities. Urogenital: Renal failure, elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS). OVERDOSAGE Overdoses involving ingestion of up to 100 capsules (20 g) have been reported. Adverse events that have been reported in association with overdosage include agitation, coma, seizures, and lethargy. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Overdosage has been reported following bolus injections or inappropriately high doses and in patients whose fluid and electrolyte balance were not properly monitored. This has resulted in elevated BUN and serum creatinine and subsequent renal failure. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION). DOSAGE AND ADMINISTRATION Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days. Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease: 400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily. The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re- evaluated to assess the need for continuation of therapy with ZOVIRAX. Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence. Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox. Adults and Children over 40 kg: 800 mg 4 times daily for 5 days. Intravenous ZOVIRAX is indicated for the treatment of varicella-zoster infections in immunocompromised patients. When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms. Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose of ZOVIRAX Capsules, Tablets, or Suspension should be modified as shown in Table 3: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 10 Table 3. Dosage Modification for Renal Impairment Creatinine Adjusted Dosage Regimen Normal Dosage Regimen Clearance (mL/min/1.73 m2) Dose (mg) Dosing Interval 200 mg every 4 hours >10 200 every 4 hours, 5x daily 0-10 200 every 12 hours 400 mg every 12 hours >10 0-10 400 200 every 12 hours every 12 hours 800 mg every 4 hours >25 800 every 4 hours, 5x daily 10-25 800 every 8 hours 0-10 800 every 12 hours Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis. Peritoneal Dialysis: No supplemental dose appears to be necessary after adjustment of the dosing interval. Bioequivalence of Dosage Forms: ZOVIRAX Suspension was shown to be bioequivalent to ZOVIRAX Capsules (n = 20) and 1 ZOVIRAX 800-mg tablet was shown to be bioequivalent to 4 ZOVIRAX 200-mg capsules (n = 24). HOW SUPPLIED ZOVIRAX Capsules (blue, opaque cap and body) containing 200 mg acyclovir and printed with “Wellcome ZOVIRAX 200.” Bottle of 100 (NDC 0173-0991-55). Unit dose pack of 100 (NDC 0173-0991-56). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Tablets (light blue, oval) containing 800 mg acyclovir and engraved with “ZOVIRAX 800.” Bottle of 100 (NDC 0173-0945-55). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Tablets (white, shield-shaped) containing 400 mg acyclovir and engraved with "ZOVIRAX" on one side and a triangle on the other side. Bottle of 100 (NDC 0173-0949-55). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Suspension (off-white, banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL). Bottle of 1 pint (473 mL) (NDC 0173-0953-96). Store at 15° to 25°C (59° to 77°F). GlaxoSmithKline This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 11 Research Triangle Park, NC 27709 2003, GlaxoSmithKline. All rights reserved. November 2003 RL-2049 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:59.034578	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18828slr029,19909slr019,20089slr018_zovirax_lbl.pdf', 'application_number': 18828, 'submission_type': 'SUPPL ', 'submission_number': 29}
11,350	January 25, 2002 1 SEARLE Daypro® (oxaprozin) Caplets 600 mg DESCRIPTION Daypro (oxaprozin) is a nonsteroidal anti-inflammatory drug (NSAID), chemically designated as 4,5-diphenyl-2- oxazole-propionic acid, and has the following chemical structure: The empirical formula for oxaprozin is C18H15NO3, and the molecular weight is 293. Oxaprozin is a white to off- white powder with a slight odor and a melting point of 162°C to 163°C. It is slightly soluble in alcohol and insoluble in water, with an octanol/water partition coefficient of 4.8 at physiologic pH (7.4). The pKa in water is 4.3. Daypro oral caplets contain 600 mg of oxaprozin. Inactive ingredients in Daypro oral caplets are microcrystalline cellulose, hydroxypropyl methylcellulose, methylcellulose, magnesium stearate, polacrilin potassium, starch, polyethylene glycol, and titanium dioxide. CLINICAL PHARMACOLOGY Pharmacodynamics: Daypro is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic properties in animal models. The mechanism of action of Daypro, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics (see Table 1): Absorption: Daypro is 95% absorbed after oral administration. Food may reduce the rate of absorption of oxaprozin, but the extent of absorption is unchanged. Antacids do not significantly affect the extent and rate of Daypro absorption. Table 1 Oxaprozin Pharmacokinetic Parameters [Mean (%CV)](1200 mg) Healthy Adults (19-78 years) Total Drug Unbound Drug Single Multiple Single Multiple N=35 N=12 N=35 N=12 Tmax (hr) 3.09 (39) 2.44 (40) 3.03 (48) 2.33 (35) Oral Clearance (L/hr/70 kg) 0.150 (24) 0.301 (29) 136 (24) 102 (45) Apparent volume of Distribution at steady state (Vd/F; L/70 kg) 11.7 (13) 16.7 (14) 6230 (28) 2420 (38) Elimination Half-life (hr) 54.9 (49) 41.4 (27) 27.8 (34) 19.5 (15) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 2 Distribution: In dose proportionality studies utilizing 600, 1200 and 1800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease in the clearance of the unbound drug. Decreased clearance of the unbound drug was related predominantly to a decrease in the volume of distribution and not an increase in the half life. This phenomenon is considered to have minimal impact on drug accumulation upon multiple dosing. The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 11-17 L/70 kg. Oxaprozin is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following repetitive once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. Oxaprozin penetrates into synovial tissues of rheumatoid arthritis patients with oxaprozin concentrations 2-fold and 3-fold greater than in plasma and synovial fluid, respectively. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties, however, the amount of oxaprozin excreted in breast milk has not been evaluated. Metabolism: Several oxaprozin metabolites have been identified in human urine or feces. Oxaprozin is primarily metabolized by the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. On chronic dosing, metabolites do not accumulate in the plasma of patients with normal renal function. Concentrations of the metabolites in plasma are very low. Oxaprozin’s metabolites do not have significant pharmacologic activity. The major ester and ether glucuronide conjugated metabolites have been evaluated along with oxaprozin in receptor binding studies and in vivo animal models and have demonstrated no activity. A small amount (<5%) of active phenolic metabolites are produced, but the contribution to overall activity is limited. Excretion: Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolite. Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant. Upon chronic dosing the accumulation half-life is approximately 22 hours. The elimination half-life is approximately twice the accumulation half-life due to increased binding and decreased clearance at lower concentrations. Special populations Pediatric patients: A population pharmacokinetic study indicated no clinically important age dependent changes in the apparent clearance of unbound oxaprozin between adult rheumatoid arthritis patients (N=40) and juvenile rheumatoid arthritis (JRA) patients (≥6 years, N=44) when adjustments were made for differences in body weight between these patient groups. The extent of protein binding of oxaprozin at various therapeutic total plasma concentrations was also similar between the adult and pediatric patient groups. Pharmacokinetic model-based estimates of daily exposure (AUC0-24) to unbound oxaprozin in JRA patients relative to adult rheumatoid arthritis patients suggest dose to body weight range relationships as shown in Table 2. No pharmacokinetic data are available for pediatric patients under 6 years of age. (see PRECAUTIONS: Pediatric use). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 3 Table 2 Dose to body weight range to achieve similar steady-state exposure (AUC0-24hr) to unbound oxaprozin in JRA patients relative to 70 kg adult rheumatoid arthritis patients administered oxaprozin 1200 mg QD1 Dose (mg) Body Weight Range (kg) 600 22 - 31 900 32-54 1200 ≥55 1Model-based nomogram derived from unbound oxaprozin steady- state drug plasma concentrations of JRA patients weighing 22.1 - 42.7 kg or ≥ 45.0 kg administered oxaprozin 600 mg or 1200 mg QD for 14 days, respectively. Geriatric: As with any NSAID, caution should be exercised in treating the elderly (65 years and older). No dosage adjustment is necessary in the elderly for pharmacokinetics reasons, although many elderly may need a reduced dose due to low body weight or disorders associated with aging. A multiple dose study comparing the pharmacokinetics of oxaprozin (1200 mg QD) in 20 young (21-44 years) adults and 20 elderly (64-83 years) adults, did not show any statistically significant differences between age groups. Race: Pharmacokinetics differences due to race have not been identified. Hepatic insufficiency: Approximately 95% of oxaprozin is metabolized by the liver. However, patients with well compensated cirrhosis do not require reduced doses of oxaprozin as compared to patients with normal hepatic function. Nevertheless, caution should be observed in patients with severe hepatic dysfunction. Cardiac failure: Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin. Renal insufficiency: The pharmacokinetics of oxaprozin have been investigated in patients with renal insufficiency. Oxaprozin’s renal clearance decreased proportionally with creatinine clearance (CrCl), but since only about 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCl. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or CAPD due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal insufficiency (see Precautions: Renal effects). CLINICAL STUDIES Rheumatoid arthritis: Daypro was evaluated for managing the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients. Daypro was given in single or divided daily doses of 600 to 1800 mg/day and was found to be comparable to 2600 to 3900 mg/day of aspirin. At these doses there was a trend (over all trials) for oxaprozin to be more effective and cause fewer gastrointestinal side effects than aspirin. Daypro was given as a once-a-day dose of 1200 mg in most of the clinical trials, but larger doses (up to 26 mg/kg or 1800 mg/day) were used in selected patients. In some patients, Daypro may be better tolerated in divided doses. Due to its long half-life, several days of Daypro therapy were needed for the drug to reach its full effect (see DOSAGE and ADMINISTRATION: Individualization of dosage). Osteoarthritis: Daypro was evaluated for the management of the signs and symptoms of osteoarthritis in a total of 616 patients in active-controlled clinical trials against aspirin (N=464), piroxicam (N=102), and other NSAIDs. Daypro was given both in variable (600 to 1200 mg/day) and in fixed (1200 mg/day) dosing schedules in either single or divided doses. In these trials, oxaprozin was found to be comparable to 2600 to 3200 mg/day doses of aspirin or 20 mg/day doses of piroxicam. Oxaprozin was effective both in once-daily and in divided dosing This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 4 schedules. In controlled clinical trials several days of oxaprozin therapy were needed for the drug to reach its full effects (see DOSAGE and ADMINISTRATION: Individualization of dosage). INDICATIONS AND USAGE Daypro is indicated for relief of the signs and symptoms of osteoarthritis, adult rheumatoid arthritis and juvenile rheumatoid arthritis. CONTRAINDICATIONS Daypro is contraindicated in patients with known hypersensitivity to oxaprozin. Daypro should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma.) WARNINGS Gastrointestinal (GI) Effects-Risk of GI Ulceration, Bleeding and Perforation Serious gastrointestinal toxicity, such as inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue thus, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age and poor general health status. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Daypro. Daypro should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Advanced Renal Disease In cases with advanced kidney disease, treatment with Daypro is not recommended. If Daypro therapy must be initiated, close monitoring of the patient’s kidney function is advisable (see PRECAUTIONS – Renal Effects). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 5 Pregnancy In late pregnancy, as with other NSAIDs, Daypro should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General Daypro cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Daypro in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Daypro. These laboratory abnormalities may progress, remain unchanged, or may be transient with continued therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminate hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Daypro. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Daypro should be discontinued. Renal effects: Caution should be used when initiating treatment with Daypro in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Daypro. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS – Advanced Renal Disease). As with other NSAIDs, long-term administration of Daypro has resulted in renal papillary necrosis and other renal medullary changes. Renal toxicity has also been seen in patients in which renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti- inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state. Daypro metabolites are eliminated primarily by the kidneys. The extent to which the metabolites may accumulate in patients with renal failure has not been studied. As with other NSAIDs, metabolites of which are excreted by the kidney, patients with significantly impaired renal function should be more closely monitored. Photosensitivity: Oxaprozin has been associated with rash and/or mild photosensitivity in dermatologic testing. An increased incidence of rash on sun-exposed skin was seen in some patients in the clinical trials. Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, including Daypro. This may be due to fluid retention, gastrointestinal blood loss, or an incompletely described effect upon erythrogenesis. Patients on long-term treatment with Daypro should have their hemoglobin or hematocrit values determined if they exhibit any signs or symptoms of anemia. All drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent with platelet function and vascular responses to bleeding. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Daypro does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 6 Daypro who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Fluid Retention and Edema: Fluid retention and edema have been observed in some patients taking NSAIDs. Therefore, as with other NSAIDs, Daypro should be used with caution in patients with fluid retention, hypertension, or heart failure. Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with the severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Daypro should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for patients: Daypro, like other drugs of its class, can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although serious gastrointestinal tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Risk of Gastrointestinal Ulceration, Bleeding and Perforation). Patients should report to their physicians the signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, weight gain, or edema. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see WARNINGS). In late pregnancy, as with other NSAIDs, Daypro should be avoided because it will cause premature closure of the ductus arteriosus. Laboratory Tests Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Daypro should be discontinued. Drug interactions Aspirin: Concomitant administration of Daypro and aspirin is not recommended because oxaprozin displaces salicylates from plasma protein binding sites. Coadministration would be expected to increase the risk of salicylate toxicity. Methotrexate: Coadministration of oxaprozin with methotrexate results in approximately a 36% reduction in apparent oral clearance of methotrexate. A reduction in methotrexate dosage may be considered due to the potential for increased methotrexate toxicity associated with the increased exposure. ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. Oxaprozin has been shown to alter the pharmacokinetics of enalapril (significant decrease in dose-adjusted AUC0- 24 and Cmax) and its active metabolite enalaprilat (significant increase in dose-adjusted AUC0-24). This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Furosemide: Clinical studies, as well as post marketing observations, have shown that Daypro can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see PRECAUTIONS, Renal Effects), as well as to assure diuretic efficacy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 7 Lithium: Coadministration of oxaprozin with lithium carbonate can cause an increase in serum lithium levels. Whenever oxaprozin is added to or removed from patients on lithium therapy, therapeutic drug monitoring of lithium levels should be performed. Glyburide: While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. Warfarin: The effects of warfarin and NSAIDs on gastrointestinal (GI) bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that of users of either drug alone. H2-receptor antagonists: The total body clearance of oxaprozin was reduced by 20% in subjects who concurrently received therapeutic doses of cimetidine or ranitidine; no other pharmacokinetic parameter was affected. A change of clearance of this magnitude lies within the range of normal variation and is unlikely to produce a clinically detectable difference in the outcome of therapy. Beta-blockers: Subjects receiving 1200 mg Daypro qd with 100 mg metoprolol bid exhibited statistically significant but transient increases in sitting and standing blood pressures after 14 days. Therefore, as with all NSAIDs, routine blood pressure monitoring should be considered in these patients when starting Daypro therapy. Other drugs: The coadministration of oxaprozin and antacids, acetaminophen, or conjugated estrogens resulted in no statistically significant changes in pharmacokinetic parameters in single- and/or multiple-dose studies. The interaction of oxaprozin with cardiac glycosides has not been studied. Laboratory test interactions: False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking Daypro. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of Daypro therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish Daypro from benzodiazepines. Carcinogenesis, mutagenesis, impairment of fertility: In oncogenicity studies, oxaprozin administration for 2 years was associated with the exacerbation of liver neoplasms (hepatic adenomas and carcinomas) in male CD mice, but not in female CD mice or rats. The significance of this species-specific finding to man is unknown. Oxaprozin did not display mutagenic potential. Results from the Ames test, forward mutation in yeast and Chinese hamster ovary (CHO) cells, DNA repair testing in CHO cells, micronucleus testing in mouse bone marrow, chromosomal aberration testing in human lymphocytes, and cell transformation testing in mouse fibroblast all showed no evidence of genetic toxicity or cell-transforming ability. Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200 mg/kg/day (1180 mg/m2); the usual human dose is 17 mg/kg/day (629 mg/m2). However, testicular degeneration was observed in beagle dogs treated with 37.5 to 150 mg/kg/day (750 to 3000 mg/m2) of oxaprozin for 6 months, or 37.5 mg/kg/day for 42 days, a finding not confirmed in other species. The clinical relevance of this finding is not known. Pregnancy: Teratogenic Effects: Pregnancy Category C. Teratology studies with oxaprozin were performed in mice, rats, and rabbits. In mice and rats, no drug-related developmental abnormalities were observed at 50 to 200 mg/kg/day of oxaprozin (225 to 900 mg/m2). However, in rabbits, infrequent malformed fetuses were observed in dams treated with 7.5 to 30 mg/kg/day of oxaprozin (the usual human dosage range). Animal reproductive studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Oxaprozin should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 8 Nonteratogenic Effects: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Daypro on labor and delivery in pregnant women are unknown. 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 Daypro, 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 of Daypro in pediatric patients less than 6 years of age have not been established. The effectiveness of Daypro for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6-16 years is supported by evidence from adequate and well controlled studies in adult rheumatoid arthritis patients, and is based on an extrapolation of the demonstrated efficacy of Daypro in adults with rheumatoid arthritis and the similarity in the course of the disease and the drug’s mechanism of effect between these two patient populations. Use of Daypro in JRA patients 6-16 years of age is also supported by the following pediatric studies. The pharmacokinetic profile and tolerability of oxaprozin were assessed in JRA patients relative to adult rheumatoid arthritis patients in a 14 day multiple dose pharmacokinetic study. Apparent clearance of unbound oxaprozin in JRA patients was reduced compared to adult rheumatoid arthritis patients, but this reduction could be accounted for by differences in body weight (see Pharmacokinetics: Pediatric patients). No pharmacokinetic data are available for pediatric patients under 6 years. Adverse events were reported by approximately 45% of JRA patients versus an approximate 30% incidence of adverse events in the adult rheumatoid arthritis patient cohort. Most of the adverse events were related to the gastrointestinal tract and were mild to moderate. In a 3 month open label study, 10 - 20 mg/kg/day of oxaprozin were administered to 59 JRA patients. Adverse events were reported by 58% of JRA patients. Most of those reported were generally mild to moderate, tolerated by the patients, and did not interfere with continuing treatment. Gastrointestinal symptoms were the most frequently reported adverse effects and occurred at a higher incidence than those historically seen in controlled studies in adults. Fifty-two patients completed 3 months of treatment with a mean daily dose of 20 mg/kg. Of 30 patients who continued treatment (19 - 48 week range total treatment duration), nine (30%) experienced rash on sun-exposed areas of the skin and 5 of those discontinued treatment. Controlled clinical trials with oxaprozin in pediatric patients have not been conducted. Geriatric use: No adjustment of the dose of Daypro is necessary in the elderly for pharmacokinetic reasons, although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging. No significant differences in the pharmacokinetic profile for oxaprozin were seen in studies in the healthy elderly. (see CLINICAL PHARMACOLOGY Special Populations). Of the total number of subjects evaluated in four placebo controlled clinical studies of oxaprozin, 39% were 65 and over, and 11% were 75 and over. No overall differences in safety or 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. Although selected elderly patients in controlled clinical trials tolerated Daypro as well as younger patients, caution should be exercised in treating the elderly, and extra care should be taken when choosing a dose. As with any NSAID, the elderly are likely to tolerate adverse reactions less well than younger patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 9 Daypro is substantially excreted by the kidney, and the risk of toxic reactions to Daypro 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 PRECAUTIONS Renal Effects). ADVERSE REACTIONS Adverse reaction data were derived from patients who received Daypro in multidose, controlled, and open-label clinical trials, and from worldwide marketing experience. Rates for events occurring in more than 1% of patients, and for most of the less common events, are based on 2253 patients who took 1200 to 1800 mg Daypro per day in clinical trials. Of these, 1721 were treated for at least 1 month, 971 for at least 3 months, and 366 for more than 1 year. Rates for the rarer events and for events reported from worldwide marketing experience are difficult to estimate accurately and are only listed as less than 1%. INCIDENCE GREATER THAN 1%: In clinical trials or in patients taking other NSAIDs (indicated by double asterisks*), the following adverse reactions occurred at an incidence greater than 1%. Reactions occurring in 3% to 9% of patients treated with Daypro are indicated by an asterisk(); those reactions occurring in less than 3% of patients are unmarked. Cardiovascular system: edema** Digestive system: abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal ulcers* (gastric/duodenal), gross bleeding/perforation, heartburn, liver enzyme elevations*, nausea, vomiting. Hematologic system: anemia, increased bleeding time Nervous system: CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep, dizziness, headache. Skin and appendages: pruritus*, rash. Special senses: tinnitus Urogenital system: abnormal renal function, dysuria or frequency. INCIDENCE LESS THAN 1%: The following adverse reactions were reported in clinical trials, from worldwide marketing experience (in italics) or in patients taking other NSAIDs (double asterisks). Body as a whole: drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis, serum sickness. Cardiovascular system: edema, blood pressure changes, congestive heart failure, hypertension, palpitations, tachycardia, syncope. Digestive system: alteration in taste, dry mouth, esophagitis, gastritis, glossitis, hematemesis, jaundice, peptic ulceration and/or GI bleeding (see WARNINGS), liver function abnormalities including hepatitis (see PRECAUTIONS), stomatitis, hemorrhoidal or rectal bleeding, pancreatitis. Hematologic system: agranulocytosis, anemia, ecchymoses, eosinophilia, melena, pancytopenia, purpura, thrombocytopenia, leukopenia. Metabolic system: weight changes. Nervous system: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo, weakness. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 10 Respiratory system: asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, symptoms of upper respiratory tract infection, respiratory depression. Skin: alopecia, angioedema, pruritus, urticaria, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, sweat, toxic epidermal necrolysis (Lyell’s syndrome). Special senses: blurred vision, conjunctivitis, hearing decrease. Urogenital: acute interstitial nephritis, cystitis, dysuria, hematuria, increase in menstrual flow, nephrotic syndrome, oliguria/polyuria, proteinuria, renal insufficiency, acute renal failure, decreased menstrual flow. DRUG ABUSE AND DEPENDENCE Daypro is a non-narcotic drug. Usually reliable animal studies have indicated that Daypro has no known addiction potential in humans. OVERDOSAGE No patient experienced either an accidental or intentional overdosage of Daypro in the clinical trials of the drug. Symptoms following acute overdose with other NSAIDs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain and are generally reversible with supportive care. Gastrointestinal bleeding and coma have occurred following NSAID overdose. Hypertension, acute renal failure, and respiratory depression are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with an osmotic cathartic. Forced diuresis, alkalization of the urine, or hemoperfusion would probably not be useful due to the high degree of protein binding of oxaprozin. DOSAGE AND ADMINISTRATION Rheumatoid arthritis: For relief of the signs and symptoms of rheumatoid arthritis, the usual recommended dose is 1200 mg (two 600-mg caplets) given orally once a day (see Individualization of dosage). Osteoarthritis: For relief of the signs and symptoms of osteoarthritis, the usual recommended dose is 1200 mg (two 600-mg caplets) given orally once a day (see Individualization of dosage). Juvenile Rheumatoid Arthritis: For the relief of the signs and symptoms of JRA in patients 6-16 years of age, the recommended dose given orally once per day should be based on body weight of the patient as given in Table 3 (see also Individualization of dosage). Table 3 Body Weight Range (kg) Dose (mg) 22 - 31 600 32-54 900 ≥55 1200 (see CLINICAL PHARMACOLOGY/Special Populations/Pediatric Patients) Individualization of dosage: As with other NSAIDs, the lowest dose should be sought for each patient. Therefore, after observing the response to initial therapy with Daypro, the dose and frequency should be adjusted to suit an individual patient’s needs. In osteoarthritis and rheumatoid arthritis and juvenile rheumatoid arthritis, the dosage should be individualized to the lowest effective dose of Daypro to minimize adverse effects. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 25, 2002 11 maximum recommended total daily dose of Daypro in adults is 1800 mg (26 mg/kg, whichever is lower) in divided doses. In children, doses greater than 1200 mg have not been studied. Patients of low body weight should initiate therapy with 600 mg once daily. Patients with severe renal impairment or on dialysis should also initiate therapy with 600 mg once daily. If there is insufficient relief of symptoms in such patients, the dose may be cautiously increased to 1200 mg, but only with close monitoring (see CLINICAL PHARMACOLOGY/Special Populations). In adults, in cases where a quick onset of action is important, the pharmacokinetics of oxaprozin allow therapy to be started with a one-time loading dose of 1200 to 1800 mg (not to exceed 26 mg/kg). Doses larger than 1200 mg/day on a chronic basis should be reserved for patients who weigh more than 50 kg, have normal renal and hepatic function, are at low risk of peptic ulcer, and whose severity of disease justifies maximal therapy. Physicians should ensure that patients are tolerating doses in the 600 to 1200 mg/day range without gastroenterologic, renal, hepatic, or dermatologic adverse effects before advancing to the larger doses. Most patients will tolerate once-a-day dosing with Daypro, although divided doses may be tried in patients unable to tolerate single doses. SAFETY AND HANDLING Daypro is supplied as a solid dosage form in closed containers, is not known to produce contact dermatitis, and poses no known risk to healthcare workers. It may be disposed of in accordance with applicable local regulations governing the disposal of pharmaceuticals. HOW SUPPLIED Daypro 600-mg caplets are white, capsule-shaped, scored, film-coated, with DAYPRO debossed on one side and 1381 on the other side. NDC Number __Size 0025-1381-31 bottle of 100 0025-1381-51 bottle of 500 0025-1381-34 carton of 100 unit dose Keep bottles tightly closed. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure. Protect the unit dose from light. Rx only (date) G.D. Searle LLC A Subsidiary of Pharmacia Corp. Chicago IL 60680 USA Address medical inquiries to: Pharmacia Healthcare Information Services 5200 Old Orchard Road Skokie IL 60077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:59.094015	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18841s12s16lbl.pdf', 'application_number': 18841, 'submission_type': 'SUPPL ', 'submission_number': 16}
11,351	DAYPRO® (oxaprozin) 600mg Caplets Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (see WARNINGS). • DAYPRO® is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAID’s cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). DESCRIPTION DAYPRO (oxaprozin) is a nonsteroidal anti-inflammatory drug (NSAID), chemically designated as 4,5-diphenyl-2-oxazole-propionic acid, and has the following chemical structure: The empirical formula for oxaprozin is C18H15NO3, and the molecular weight is 293. Oxaprozin is a white to off-white powder with a slight odor and a melting point of 162°C to 163°C. It is slightly soluble in alcohol and insoluble in water, with an octanol/water partition coefficient of 4.8 at physiologic pH (7.4). The pKa in water is 4.3. Daypro oral caplets contain 600 mg of oxaprozin. Inactive ingredients in Daypro oral caplets are microcrystalline cellulose, hypromellose, methylcellulose, magnesium stearate, polacrilin potassium, starch, polyethylene glycol, and titanium dioxide. CLINICAL PHARMACOLOGY Pharmacodynamics: DAYPRO is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic properties in animal models. The mechanism of action of DAYPRO, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics (see Table 1) Absorption: DAYPRO is 95% absorbed after oral administration. Food may reduce the rate of absorption of oxaprozin, but the extent of absorption is unchanged. Antacids do not significantly affect the extent and rate of DAYPRO absorption. Table 1 Oxaprozin Pharmacokinetic Parameters [Mean (%CV)](1200 mg) Healthy Adults (19-78 years) Total Drug Unbound Drug Single Multiple Single Multiple N=35 N=12 N=35 N=12 Tmax (hr) 3.09 (39) 2.44 (40) 3.03 (48) 2.33 (35) Oral Clearance 0.150 (24) 0.301 (29) 136 (24) 102 (45) (L/hr/70 kg) Apparent Volume 11.7 (13) 16.7 (14) 6230 (28) 2420 (38) of Distribution at Steady State (Vd/F; L/70 kg) Elimination 54.9 (49) 41.4 (27) 27.8 (34) 19.5 (15) Half-life (hr) Distribution: In dose proportionality studies utilizing 600, 1200 and 1800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease in the clearance of the unbound drug. Decreased clearance of the unbound drug was related predominantly to a decrease in the volume of distribution and not an increase in the half-life. This phenomenon is considered to have minimal impact on drug accumulation upon multiple dosing. The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 11-17 L/70 kg. Oxaprozin is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following repetitive once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. Oxaprozin penetrates into synovial tissues of rheumatoid arthritis patients with oxaprozin concentrations 2-fold and 3-fold greater than in plasma and synovial fluid, respectively. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties; however, the amount of oxaprozin excreted in breast milk has not been evaluated. Metabolism: Several oxaprozin metabolites have been identified in human urine or feces. Oxaprozin is primarily metabolized by the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. On chronic dosing, metabolites do not accumulate in the plasma of patients with normal renal function. Concentrations of the metabolites in plasma are very low. Oxaprozin’s metabolites do not have significant pharmacologic activity. The major ester and ether glucuronide conjugated metabolites have been evaluated along with oxaprozin in receptor binding studies and in vivo animal models and have demonstrated no activity. A small amount (<5%) of active phenolic metabolites are produced, but the contribution to overall activity is limited. Excretion: Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolite. Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant. Upon chronic dosing the accumulation half-life is approximately 22 hours. The elimination half-life is approximately twice the accumulation half-life due to increased binding and decreased clearance at lower concentrations. Special populations Pediatric patients: A population pharmacokinetic study indicated no clinically important age dependent changes in the apparent clearance of unbound oxaprozin between adult rheumatoid arthritis patients (N=40) and juvenile rheumatoid arthritis (JRA) patients (≥6 years, N=44) when adjustments were made for differences in body weight between these patient groups. The extent of protein binding of oxaprozin at various therapeutic total plasma concentrations was also similar between the adult and pediatric patient groups. Pharmacokinetic model-based estimates of daily exposure (AUC0-24) to unbound oxaprozin in JRA patients relative to adult rheumatoid arthritis patients suggest dose to body weight range relationships as shown in Table 2. No pharmacokinetic data are available for pediatric patients under 6 years of age (see PRECAUTIONS, Pediatric use). Table 2 Dose to body weight range to achieve similar steady-state exposure (AUC0-24hr) to unbound oxaprozin in JRA patients relative to 70 kg adult rheumatoid arthritis patients administered oxaprozin 1200 mg QD1 Dose (mg) Body WeightRange (kg) 600 22 –31 900 32 –54 1200 ≥ 55 1Model-based nomogram derived from unbound oxaprozin steady-state drug plasma concentrations of JRA patients weighing 22.1 – 42.7 kg or ≥45.0 kg administered oxaprozin 600 mg or 1200 mg QD for 14 days, respectively. Geriatric: As with any NSAID, caution should be exercised in treating the elderly (65 years and older). No dosage adjustment is necessary in the elderly for pharmacokinetics reasons, although many elderly may need a reduced dose due to low body weight or disorders associated with aging. A multiple dose study comparing the pharmacokinetics of oxaprozin (1200 mg QD) in 20 young (21- 44 years) adults and 20 elderly (64-83 years) adults did not show any statistically significant differences between age groups. Race: Pharmacokinetics differences due to race have not been identified. Hepatic insufficiency: Approximately 95% of oxaprozin is metabolized by the liver. However, patients with well-compensated cirrhosis do not require reduced doses of oxaprozin as compared to patients with normal hepatic function. Nevertheless, caution should be observed in patients with severe hepatic dysfunction. Cardiac failure: Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin. Renal insufficiency: The pharmacokinetics of oxaprozin have been investigated in patients with renal insufficiency. Oxaprozin’s renal clearance decreased proportionally with creatinine This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda clearance (CrCl), but since only about 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCl. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal insufficiency (see WARNINGS, Renal effects). CLINICAL STUDIES Rheumatoid arthritis: DAYPRO was evaluated for managing the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients. DAYPRO was given in single or divided daily doses of 600 to 1800 mg/day and was found to be comparable to 2600 to 3900 mg/day of aspirin. At these doses there was a trend (over all trials) for oxaprozin to be more effective and cause fewer gastrointestinal side effects than aspirin. DAYPRO was given as a once-a-day dose of 1200 mg in most of the clinical trials, but larger doses (up to 26 mg/kg or 1800 mg/day) were used in selected patients. In some patients, DAYPRO may be better tolerated in divided doses. Due to its long half-life, several days of Daypro therapy were needed for the drug to reach its full effect (see DOSAGE AND ADMINISTRATION, Individualization of dosage). Osteoarthritis: DAYPRO was evaluated for the management of the signs and symptoms of osteoarthritis in a total of 616 patients in active controlled clinical trials against aspirin (N=464), piroxicam (N=102), and other NSAIDs. Daypro was given both in variable (600 to 1200 mg/day) and in fixed (1200 mg/day) dosing schedules in either single or divided doses. In these trials, oxaprozin was found to be comparable to 2600 to 3200 mg/day doses of aspirin or 20 mg/day doses of piroxicam. Oxaprozin was effective both in once daily and in divided dosing schedules. In controlled clinical trials several days of oxaprozin therapy were needed for the drug to reach its full effects (see DOSAGE AND ADMINISTRATION, Individualization of dosage). INDICATIONS AND USAGE Carefully consider the potential benefits and risks of DAYPRO and other treatment options before deciding to use DAYPRO. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). DAYPRO is indicated: • For relief of the signs and symptoms of osteoarthritis • For relief of the signs and symptoms of rheumatoid arthritis • For relief of the signs and symptoms of juvenile rheumatoid arthritis CONTRAINDICATIONS DAYPRO is contraindicated in patients with known hypersensitivity to oxaprozin. DAYPRO should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions and PRECAUTIONS, Preexisting asthma). DAYPRO is contraindicated for the treatment of peri-operative pain in the setting of coronary artery This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda bypass graft (CABG) surgery (see WARNINGS). WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding and Perforation). Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension NSAIDs including DAYPRO, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including DAYPRO, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. DAYPRO should be used with caution in patients with fluid retention or heart failure. Gastrointestinal Effects–Risk of Ulceration, Bleeding, and Perforation NSAIDs, including DAYPRO, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti- inflammatory drug may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced renal disease No information is available form controlled clinical studies regarding the use of DAYPRO in patients with advanced renal disease. Therefore, treatment with DAYPRO is not recommended in these patients with advanced renal disease. If DAYPRO therapy must be initiated, close monitoring of the patients renal function is advisable. Anaphylactoid reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to DAYPRO. DAYPRO should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including DAYPRO, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, DAYPRO should be avoided because it may cause premature closure of the ductus arteriosus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General DAYPRO cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of DAYPRO in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including DAYPRO. These laboratory abnormalities may progress, remain unchanged, or may be transient with continued therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminate hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with DAYPRO. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), DAYPRO should be discontinued. Photosensitivity: Oxaprozin has been associated with rash and/or mild photosensitivity in dermatologic testing. An increased incidence of rash on sun-exposed skin was seen in some patients in the clinical trials. Hematological effects: Anemia is sometimes seen in patients receiving NSAIDs, including DAYPRO. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythrogenesis. Patients on long-term treatment with DAYPRO should have their hemoglobin or hematocrit values determined if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving DAYPRO who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin- sensitive asthma has been associated with the severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, DAYPRO should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for patients: Patients should be informed of the following information before initiating therapy with an This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. • DAYPRO, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). • DAYPRO, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding and Perforation). • DAYPRO, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. • Patients should promptly report, signs or symptoms of unexplained weight gain, or edema to their physicians. • Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. • Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactoid reactions). • In late pregnancy, as with other NSAIDs, DAYPRO should be avoided because it may cause premature closure of the ductus arteriosus. Laboratory tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs of symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, DAYPRO should be discontinued. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug interactions Aspirin Concomitant administration of DAYPRO and aspirin is not recommended because oxaprozin displaces salicylates from plasma protein binding sites. Coadministration would be expected to increase the risk of salicylate toxicity. As with other NSAIDs, concomitant administration of oxaprozin and aspirin is not generally recommended because of the potential for increased adverse effects. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Coadministration of oxaprozin with methotrexate results in approximately a 36% reduction in apparent oral clearance of methotrexate. A reduction in methotrexate dosage may be considered due to the potential for increased methotrexate toxicity associated with the increased exposure. ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. Oxaprozin has been shown to alter the pharmacokinetics of enalapril (significant decrease in dose-adjusted AUC0-24 and Cmax) and its active metabolite enalaprilat (significant increase in dose-adjusted AUC0- 24). This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Diuretics Clinical studies, as well as post marketing observations, have shown that DAYPRO can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal effects), as well as to assure diuretic efficacy. Lithium DAYPRO, like other NSAIDs, has produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%.These effects have been attributed to inhibition of renal prostaglandin synthesis by the nonsteroidal anti-inflammatory drug. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Glyburide While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. However, it is advisable to monitor patients’ blood glucose in the beginning phase of glyburide and oxaprozin cotherapy. Warfarin The effects of warfarin and NSAIDs on gastrointestinal (GI) bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that of users of either drug alone. H2-receptor antagonists The total body clearance of oxaprozin was reduced by 20% in subjects who concurrently received This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda therapeutic doses of cimetidine or ranitidine; no other pharmacokinetic parameter was affected. A change of clearance of this magnitude lies within the range of normal variation and is unlikely to produce a clinically detectable difference in the outcome of therapy. Beta-blockers Subjects receiving 1200 mg DAYPRO QD with 100 mg metoprolol bid exhibited statistically significant but transient increases in sitting and standing blood pressures after 14 days. Therefore, as with all NSAIDs, routine blood pressure monitoring should be considered in these patients when starting DAYPRO therapy. Other drugs The coadministration of oxaprozin and antacids, acetaminophen, or conjugated estrogens resulted in no statistically significant changes in pharmacokinetic parameters in single- and/or multiple-dose studies. The interaction of oxaprozin with cardiac glycosides has not been studied Laboratory test interactions False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking DAYPRO. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of DAYPRO therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish DAYPRO from benzodiazepines. Carcinogenesis, Mutagenesis, Impairment of Fertility In oncogenicity studies, oxaprozin administration for 2 years was associated with the exacerbation of liver neoplasms (hepatic adenomas and carcinomas) in male CD mice, but not in female CD mice or rats. The significance of this species-specific finding to man is unknown. Oxaprozin did not display mutagenic potential. Results from the Ames test, forward mutation in yeast and Chinese hamster ovary (CHO) cells, DNA repair testing in CHO cells, micronucleus testing in mouse bone marrow, chromosomal aberration testing in human lymphocytes, and cell transformation testing in mouse fibroblast all showed no evidence of genetic toxicity or cell-transforming ability. Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200 mg/kg/day (1180 mg/m2); the usual human dose is 17 mg/kg/day (629 mg/m2). However, testicular degeneration was observed in beagle dogs treated with 37.5 to 150 mg/kg/day (750 to 3000 mg/m2) of oxaprozin for 6 months, or 37.5 mg/kg/day for 42 days, a finding not confirmed in other species. The clinical relevance of this finding is not known. Pregnancy Teratogenic effects—Pregnancy Category C Teratology studies with oxaprozin were performed in mice, rats, and rabbits. In mice and rats, no drug-related developmental abnormalities were observed at 50 to 200 mg/kg/day of oxaprozin (225 to 900 mg/m2). However, in rabbits, infrequent malformed fetuses were observed in dams treated with 7.5 to 30 mg/kg/day of oxaprozin (the usual human dosage range). Animal reproductive studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Oxaprozin should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Nonteratogenic effects Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of DAYPRO on labor and delivery in pregnant women are unknown. Nursing mothers It is not known whether this drug is excreted in human milk; however, oxaprozin was found in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DAYPRO, 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 6 years of age have not been established. The effectiveness of DAYPRO for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6-16 years is supported by evidence from adequate and well controlled studies in adult rheumatoid arthritis patients, and is based on an extrapolation of the demonstrated efficacy of DAYPRO in adults with rheumatoid arthritis and the similarity in the course of the disease and the drug’s mechanism of effect between these two patient populations. Use of DAYPRO in JRA patients 6-16 years of age is also supported by the following pediatric studies. The pharmacokinetic profile and tolerability of oxaprozin were assessed in JRA patients relative to adult rheumatoid arthritis patients in a 14 day multiple dose pharmacokinetic study. Apparent clearance of unbound oxaprozin in JRA patients was reduced compared to adult rheumatoid arthritis patients, but this reduction could be accounted for by differences in body weight (see Pharmacokinetics, Pediatric patients). No pharmacokinetic data are available for pediatric patients under 6 years. Adverse events were reported by approximately 45% of JRA patients versus an approximate 30% incidence of adverse events in the adult rheumatoid arthritis patient cohort. Most of the adverse events were related to the gastrointestinal tract and were mild to moderate. In a 3 month open label study, 10 - 20 mg/kg/day of oxaprozin were administered to 59 JRA patients. Adverse events were reported by 58% of JRA patients. Most of those reported were generally mild to moderate, tolerated by the patients, and did not interfere with continuing treatment. Gastrointestinal symptoms were the most frequently reported adverse effects and occurred at a higher incidence than those historically seen in controlled studies in adults. Fifty-two patients completed 3 months of treatment with a mean daily dose of 20 mg/kg. Of 30 patients who continued treatment (19 - 48 week range total treatment duration), nine (30%) experienced rash on sun-exposed areas of the skin and 5 of those discontinued treatment. Controlled clinical trials with oxaprozin in pediatric patients have not been conducted. Geriatric use No adjustment of the dose of DAYPRO is necessary in the elderly for pharmacokinetic reasons, although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging. No significant differences in the pharmacokinetic profile for oxaprozin were seen in studies in the healthy elderly (see CLINICAL PHARMACOLOGY, Special populations). Of the total number of subjects evaluated in four placebo controlled clinical studies of oxaprozin, 39% were 65 and over, and 11% were 75 and over. No overall differences in safety or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. Although selected elderly patients in controlled clinical trials tolerated as well as younger patients, caution should be exercised in treating the elderly, and extra care should be taken when choosing a dose. As with any NSAID, the elderly are likely to tolerate adverse reactions less well than younger patients. DAYPRO is substantially excreted by the kidney, and the risk of toxic reactions to DAYPRO 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 WARNINGS, Renal effects). ADVERSE REACTIONS Adverse reaction data were derived from patients who received DAYPRO in multidose, controlled, and open-label clinical trials, and from worldwide marketing experience. Rates for events occurring in more than 1% of patients, and for most of the less common events, are based on 2253 patients who took 1200 to 1800 mg DAYPRO per day in clinical trials. Of these, 1721 were treated for at least 1 month, 971 for at least 3 months, and 366 for more than 1 year. Rates for the rarer events and for events reported from worldwide marketing experience are difficult to estimate accurately and are only listed as less than 1%. INCIDENCE GREATER THAN 1%: In clinical trials of DAYPRO or in patients taking other NSAIDs, the following adverse reactions occurred at an incidence greater than 1%. Cardiovascular system: edema. Digestive system: abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal ulcers (gastric/duodenal), gross bleeding/perforation, heartburn, liver enzyme elevations, nausea, vomiting. Hematologic system: anemia, increased bleeding time. Nervous system: CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep, dizziness, headache. Skin and appendages: pruritus, rash. Special senses: tinnitus. Urogenital system: abnormal renal function, dysuria or frequency. INCIDENCE LESS THAN 1%: The following adverse reactions were reported in clinical trials, from worldwide marketing experience (in italics) or in patients taking other NSAIDs. Body as a whole: appetite changes, death, drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis, serum sickness. Cardiovascular system: arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, tachycardia, syncope, vasculitis. Digestive system: alteration in taste, dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, jaundice, liver function abnormalities including hepatitis, liver failure, stomatitis, hemorrhoidal or rectal bleeding, pancreatitis. Hematologic system: agranulocytosis, aplastic anemia, ecchymoses, eosinophilia, hemolytic anemia, lymphadenopathy, melena, pancytopenia, purpura, thrombocytopenia, leukopenia. Metabolic system: hyperglycemia, weight changes. Nervous system: anxiety, asthenia, coma, convulsions, dream abnormalities, drowsiness, hallucinations, insomnia, malaise, meningitis, nervousness, paresthesia, tremors, vertigo, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda weakness. Respiratory system: asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, symptoms of upper respiratory tract infection, respiratory depression. Skin: alopecia, angioedema, urticaria, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, sweat, toxic epidermal necrolysis (Lyell’s syndrome). Special senses: blurred vision, conjunctivitis, hearing decrease. Urogenital: acute interstitial nephritis, cystitis, hematuria, increase in menstrual flow, nephrotic syndrome, oliguria/ polyuria, proteinuria, renal insufficiency, acute renal failure, decreased menstrual flow. DRUG ABUSE AND DEPENDENCE DAYPRO is a non-narcotic drug. Usually reliable animal studies have indicated that DAYPRO has no known addiction potential in humans. OVERDOSAGE No patient experienced either an accidental or intentional overdosage of DAYPRO in the clinical trials of the drug. Symptoms following acute overdose with other NSAIDs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain and are generally reversible with supportive care. Gastrointestinal bleeding and coma have occurred following NSAID overdose. Hypertension, acute renal failure, and respiratory depression are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with an osmotic cathartic. Forced diuresis, alkalization of the urine, or hemoperfusion would probably not be useful due to the high degree of protein binding of oxaprozin. DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of DAYPRO and other treatment options before deciding to use DAYPRO. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with DAYPRO, the dose and frequency should be adjusted to suit an individual patient’s needs. Rheumatoid arthritis: For relief of the signs and symptoms of rheumatoid arthritis, the usual recommended dose is 1200 mg (two 600-mg caplets) given orally once a day (see Individualization of dosage). Osteoarthritis: For relief of the signs and symptoms of osteoarthritis, the usual recommended dose is 1200 mg (two 600-mg caplets) given orally once a day (see Individualization of dosage). Juvenile rheumatoid arthritis: For the relief of the signs and symptoms of JRA in patients 6-16 years of age, the recommended dose given orally once per day should be based on body weight of the patient as given in Table 3 (see also Individualization of dosage). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3 Body Weight Range (kg) Dose (mg) 22–31 600 32–54 900 ≥55 1200 (see CLINICAL PHARMACOLOGY, Special populations: Pediatric patients) Individualization of dosage: As with other NSAIDs, the lowest dose should be sought for each patient. Therefore, after observing the response to initial therapy with DAYPRO, the dose and frequency should be adjusted to suit an individual patient’s needs. In osteoarthritis and rheumatoid arthritis and juvenile rheumatoid arthritis, the dosage should be individualized to the lowest effective dose of DAYPRO to minimize adverse effects. The maximum recommended total daily dose of DAYPRO in adults is 1800 mg (26 mg/kg, whichever is lower) in divided doses. In children, doses greater than 1200 mg have not been studied. Patients of low body weight should initiate therapy with 600 mg once daily. Patients with severe renal impairment or on dialysis should also initiate therapy with 600 mg once daily. If there is insufficient relief of symptoms in such patients, the dose may be cautiously increased to 1200 mg, but only with close monitoring (see CLINICAL PHARMACOLOGY, Special populations). In adults, in cases where a quick onset of action is important, the pharmacokinetics of oxaprozin allows therapy to be started with a one-time loading dose of 1200 to 1800 mg (not to exceed 26 mg/kg). Doses larger than 1200 mg/day on a chronic basis should be reserved for patients who weigh more than 50 kg, have normal renal and hepatic function, are at low risk of peptic ulcer, and whose severity of disease justifies maximal therapy. Physicians should ensure that patients are tolerating doses in the 600 to 1200 mg/day range without gastroenterologic, renal, hepatic, or dermatologic adverse effects before advancing to the larger doses. Most patients will tolerate once-a- day dosing with DAYPRO, although divided doses may be tried in patients unable to tolerate single doses. SAFETY AND HANDLING DAYPRO is supplied as a solid dosage form in closed containers, is not known to produce contact dermatitis, and poses no known risk to healthcare workers. It may be disposed of in accordance with applicable local regulations governing the disposal of pharmaceuticals. HOW SUPPLIED DAYPRO 600-mg caplets are white, capsule-shaped, scored, film-coated, with DAYPRO debossed on one side and 1381 on the other side. NDC Number Size 0025-1381-31 bottle of 100 0025-1381-51 bottle of 500 0025-1381-34 carton of 100 unit dose Keep bottles tightly closed. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure. Protect the unit dose from light. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DAYPRO® oxaprozin caplets LAB-0189-6.0 Revised January 2007 Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG)." NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: • can happen without warning symptoms • may cause death The chance of a person getting an ulcer or bleeding increases with: • taking medicines called “corticosteroids” and “anticoagulants” • longer use • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are use to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as: • different types of arthritis • menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider: • about all of your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness Get emergency help right away if you have any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • skin rash or blisters with fever • unusual weight gain • swelling of the arms and legs, hands and feet This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over – the –counter). Talk to your healthcare provider before using over –the –counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 Flurbiprofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 *Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke This Medication Guide has been approved by the U.S. Food and Drug Administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:59.306765	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/18841s022lbl.pdf', 'application_number': 18841, 'submission_type': 'SUPPL ', 'submission_number': 22}
11,354	CALCIJEX® (calcitriol injection) 1 mcg/mL DESCRIPTION Calcijex (calcitriol injection) is synthetically manufactured calcitriol and is available as a sterile, isotonic, clear, colorless to yellow, aqueous solution for intravenous injection. Calcijex is available in 1 mL ampuls. Each 1 mL contains calcitriol, 1 mcg; Polysorbate 20, 4 mg; sodium ascorbate 2.5 mg added. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. pH is 6.5 (5.9 to 7.0). Contains no more than 1 mcg/mL of aluminum. Calcitriol is a crystalline compound which occurs naturally in humans. It is soluble in organic solvents but relatively insoluble in water. Calcitriol is chemically designated (5Z,7E)-9, 10-secocholesta-5,7,10(19)-triene-1α,3β,25-triol and has the following structural formula: chemical structure Molecular Formula: C27H44O3 The other names frequently used for calcitriol are 1α,25-dihydroxycholecalciferol, 1α,25-dihydroxyvitamin D3, 1,25-DHCC, 1,25(OH)2D3 and 1,25-diOHC. Reference ID: 3099850 CLINICAL PHARMACOLOGY Calcitriol is the active form of vitamin D3 (cholecalciferol). The natural or endogenous supply of vitamin D in man mainly depends on ultraviolet light for conversion of 7-dehydrocholesterol to vitamin D3 in the skin. Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active on its target tissues. The initial transformation is catalyzed by a vitamin D3-25-hydroxylase enzyme present in the liver, and the product of this reaction is 25-(OH)D3 (calcifediol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D3-1-α hydroxylase to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3. The known sites of action of calcitriol are intestine, bone, kidney and parathyroid gland. Calcitriol is the most active known form of vitamin D3 in stimulating intestinal calcium transport. In acutely uremic rats, calcitriol has been shown to stimulate intestinal calcium absorption. In bone, calcitriol, in conjunction with parathyroid hormone, stimulates resorption of calcium; and in the kidney, calcitriol increases the tubular reabsorption of calcium. In vitro and in vivo studies have shown that calcitriol directly suppresses secretion and synthesis of PTH. A vitamin D-resistant state may exist in uremic patients because of the failure of the kidney to adequately convert precursors to the active compound, calcitriol. Calcitriol when administered by bolus injection is rapidly available in the blood stream. Vitamin D metabolites are known to be transported in blood, bound to specific plasma proteins. The pharmacologic activity of an administered dose of calcitriol is about 3 to 5 days. Two metabolic pathways for calcitriol have been identified, conversion to 1,24,25-(OH)3D3 and to calcitroic acid. INDICATIONS AND USAGE Calcijex (calcitriol injection) is indicated in the management of hypocalcemia in patients undergoing chronic renal dialysis. It has been shown to significantly reduce elevated parathyroid hormone levels. Reduction of PTH has been shown to result in an improvement in renal osteodystrophy. CONTRAINDICATIONS Calcijex (calcitriol injection) should not be given to patients with hypercalcemia or evidence of vitamin D toxicity. Calcijex (calcitriol injection) is contraindicated in patients with previous hypersensitivity to calcitriol or any of its excipients. WARNINGS Since calcitriol is the most potent metabolite of vitamin D available, prescription-based doses of vitamin D and its derivatives should be withheld or used with caution during treatment to avoid the risk of hypercalcemia. A non-aluminum phosphate-binding compound should be used to control serum phosphorus levels in patients undergoing dialysis. Reference ID: 3099850 Overdosage of any form of vitamin D is dangerous (see also OVERDOSAGE). Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis and other soft-tissue calcification. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2/dL2. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition. PRECAUTIONS General Excessive dosage of Calcijex (calcitriol injection) induces hypercalcemia and in some instances hypercalciuria; therefore, early in treatment during dosage adjustment, serum calcium and phosphorus should be determined at least twice weekly. Should hypercalcemia develop, the drug should be discontinued immediately. Calcijex should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias. Information for the Patient The patient and his or her parents should be informed about adherence to instructions about diet and calcium supplementation and avoidance of the use of unapproved non-prescription drugs, including magnesium- containing antacids. Patients should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS). Essential Laboratory Tests Serum calcium, phosphorus, magnesium and alkaline phosphatase and 24-hour urinary calcium and phosphorus should be determined periodically. During the initial phase of the medication, serum calcium and phosphorus should be determined more frequently (twice weekly). Adynamic bone disease may develop if PTH levels are suppressed to abnormal levels. If biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. If PTH levels fall below recommended target range (1.5 to 3 times the upper limit of normal), in patients treated with Calcijex, the Calcijex dose should be reduced or therapy discontinued. Discontinuation of Calcijex therapy may result in rebound effect, therefore, appropriate titration downward to a maintenance dose is recommended. Drug Interactions Concomitant use of magnesium-containing preparations should be used with caution or avoided since such use may lead to the development of hypermagnesemia. Corticosteroids with glucocorticoid activity may counteract the bone and mineral metabolism effects of vitamin D analogues. Reference ID: 3099850 Cytochrome P450 enzyme-inducing anticonvulsants such as carbamazepine, phenobarbital and phenytoin may reduce the effects of vitamin D because they increase vitamin D catabolism. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of Calcijex (calcitriol injection). Calcitriol was not mutagenic in vitro in the Ames Test nor was oral calcitriol genotoxic in vivo in the Mouse Micronucleus Test. No significant effects on fertility and/or general reproductive performances were observed in a Segment I study in rats using oral calcitriol at doses of up to 0.3 mcg/kg. Pregnancy Teratogenic Effects Pregnancy Category C Calcitriol has been found to be teratogenic in rabbits when given orally at doses of 0.08 and 0.3 mcg/kg. All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 fetuses) showed external and skeletal abnormalities compared with controls. Teratogenicity studies in rats at doses up to 0.45 mcg/kg orally showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcijex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects In the rabbit, oral dosages of 0.3 mcg/kg/day administered on days 7 to 18 of gestation resulted in 19% maternal mortality, a decrease in mean fetal body weight and a reduced number of newborns surviving to 24 hours. A study of the effects on orally administered calcitriol on peri-and postnatal development in rats resulted in hypercalcemia in the offspring of dams given calcitriol at doses of 0.08 or 0.3 mcg/kg/day, hypercalcemia and hypophosphatemia in dams given calcitriol at a dose of 0.08 or 0.3 mcg/kg/day and increased serum urea nitrogen in dams given calcitriol at a dose of 0.3 mcg/kg/day. In another study in rats, maternal weight gain was slightly reduced at an oral dose of 0.3 mcg/kg/day administered on days 7 to 15 of gestation. The offspring of a woman administered oral calcitriol at 17 to 36 mcg/day during pregnancy manifested mild hypercalcemia in the first 2 days of life which returned to normal at day 3. 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 calcitriol, 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: 3099850 Pediatric Use The safety and effectiveness of Calcijex were examined in a 12-week randomized, double-blind, placebo- controlled study of 35 pediatric patients, aged 13-18 years, with end-stage renal disease on hemodialysis. Sixty-six percent of the patients were male, 57% were African-American, and nearly all had received some form of vitamin D therapy prior to the study. The initial dose of Calcijex was 0.5 mcg, 1.0 mcg, or 1.5 mcg, 3 times per week, based on baseline iPTH level of less than 500 pg/mL, 500-1000 pg/mL, or greater than 1000 pg/mL, respectively. The dose of Calcijex was adjusted in 0.25 mcg increments based on the levels of serum iPTH, calcium, and Ca x P. The mean baseline levels of iPTH were 769 pg/mL for the 16 Calcijex-treated patients and 897 pg/mL for the 19 placebo-treated subjects. The mean weekly dose of Calcijex ranged from 1.0 mcg to 1.4 mcg. In the primary efficacy analysis, 7 of 16 (44%) subjects in the Calcijex group had 2 consecutive 30% decreases from baseline iPTH compared with 3 of 19 (16%) patients in the placebo group (95% CI for the difference between groups -6%, 62%). One Calcijex-treated patient experienced transient hypercalcemia (> 11.0 mg/dL), while 6 of 16 (38%) Calcijex-treated patients vs. 2 of 19 (11%) placebo- treated patients experienced Ca x P > 75. Geriatric Use Clinical studies of Calcijex 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 effects of Calcijex (calcitriol injection) are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include: Early Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, metallic taste, anorexia, abdominal pain and epigastric discomfort. Late Polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias, nephrocalcinosis, sensory disturbance, dehydration, apathy, and, rarely, overt psychosis. Occasional mild pain on injection has been observed. Reference ID: 3099850 Post-Marketing Experience Rare cases of hypersensitivity reactions have been reported, including anaphylaxis. OVERDOSAGE Administration of Calcijex (calcitriol injection) to patients in excess of their requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia. High intake of calcium and phosphate concomitant with Calcijex may lead to similar abnormalities (see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS). Treatment of Hypercalcemia and Overdosage in Patients on Hemodialysis General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of normal range) consists of immediate discontinuation of Calcijex therapy, institution of a low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until normocalcemia ensues. Hypercalcemia usually resolves in two to seven days. When serum calcium levels have returned to within normal limits, Calcijex therapy may be reinstituted at a dose 0.5 mcg less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes. Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate. Treatment of Accidental Overdosage of Calcitriol Injection The treatment of acute accidental overdosage of Calcijex should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and low calcium diet are also indicated in accidental overdosage. Due to the relatively short duration of the pharmacological action of calcitriol, further measures are probably unnecessary. Should, however, persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives which may be considered, depending on the patients' underlying condition. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis. The use of peritoneal dialysis against a calcium-free dialysate has also been reported. DOSAGE AND ADMINISTRATION Calcijex is for intravenous injection only. The optimal dose of Calcijex (calcitriol injection) must be carefully determined for each patient. The effectiveness of Calcijex therapy is predicated on the assumption that each patient is receiving an adequate and appropriate daily intake of calcium. The RDA for calcium in adults is 800 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures. Reference ID: 3099850 The recommended initial dose of Calcijex, depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1 mcg (0.02 mcg/kg) to 2 mcg administered intravenously three times weekly, approximately every other day. Doses as small as 0.5 mcg and as large as 4 mcg three times weekly have been used as an initial dose. If a satisfactory response is not observed, the dose may be increased by 0.5 to 1 mcg at two to four week intervals. During this titration period, serum calcium and phosphorus levels should be obtained at least twice weekly. If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate. Then, the Calcijex dose should be reinitiated at a lower dose. Doses may need to be reduced as the PTH levels decrease in response to the therapy. Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels. The following is a suggested approach in dose titration: PTH Levels Calcijex Dose the same or increasing increase decreasing by < 30% increase decreasing by > 30%, < 60% maintain decreasing by > 60% decrease one and one-half to three times maintain the upper limit of normal Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard unused portion. HOW SUPPLIED Calcijex (calcitriol injection) is supplied as follows: List Container Concentration Fill 8110 Ampul 1 mcg/mL 1 mL Protect from light. Store at 20o – 25oC (68o – 77oF); excursions permitted to 15o - 30oC (59o - 86oF) [see USP Controlled Room Temperature] Mfd. by: Hospira, Inc. Lake Forest, IL 60045 USA For: Abbott Laboratories Reference ID: 3099850 North Chicago, IL 60064 USA ©Abbott 2012 Printed in USA Revised: 03/2012 Reference ID: 3099850	custom-source	2025-02-12T13:44:59.432118	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018874s022lbl.pdf', 'application_number': 18874, 'submission_type': 'SUPPL ', 'submission_number': 22}
11,353	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INDOMETHACIN CAPSULES safely and effectively. See full prescribing information for INDOMETHACIN CAPSULES. INDOMETHACIN capsules, for oral use Initial U.S. Approval: 1965 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning.  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1)  Indomethacin capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1)  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) ----------------------RECENT MAJOR CHANGES------------------------------ Boxed Warning 5/2016 Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 5/2016 Warnings and Precautions, Heart Failure and Edema (5.5) 5/2016 ---------------------------INDICATIONS AND USAGE---------------------------- Indomethacin capsules are a nonsteroidal anti-inflammatory drug indicated for (1)  Moderate to severe rheumatoid arthritis including acute flares of chronic disease  Moderate to severe ankylosing spondylitis  Moderate to severe osteoarthritis  Acute painful shoulder (bursitis and/or tendinitis)  Acute gouty arthritis ------------------DOSAGE AND ADMINISTRATION---------------------------  Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1)  The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis, is 25 mg two or three times a day. (2.2)  The dosage for acute painful shoulder (bursitis and/or tendinitis) is: 75 mg to 150 mg daily in 3 or 4 divided doses (2.3)  The dosage for acute gouty arthritis: is 50 mg three times a day, until pain is tolerable (2.4) ----------------DOSAGE FORMS AND STRENGTHS-------------------------- Indomethacin capsules: 25 mg (3) -------------------------CONTRAINDICATIONS----------------------------------  Known hypersensitivity to indomethacin or any components of the drug product (4)  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4)  In the setting of CABG surgery (4) ------------------WARNINGS AND PRECAUTIONS----------------------------  Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3)  Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7)  Heart Failure and Edema: Avoid use of indomethacin capsules in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5)  Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of indomethacin capsules in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6)  Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7)  Exacerbation of Asthma Related to Aspirin Sensitivity: Indomethacin capsules are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8)  Serious Skin Reactions: Discontinue indomethacin capsules at first appearance of skin rash or other signs of hypersensitivity (5.9)  Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30 weeks gestation (5.10, 8.1)  Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.11, 7) ------------------------------ADVERSE REACTIONS------------------------------ Most common adverse reactions in trials (>3%) are headache, dizziness, dyspepsia, and nausea (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1 800-FDA-1088 or www.fda.gov/medwatch. ----------------------------DRUG INTERACTIONS-------------------------------  Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking indomethacin capsules with drugs that interfere with hemostasis. Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended (7)  ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta- Blockers: Concomitant use with indomethacin capsules may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7)  ACE Inhibitors and ARBs: Concomitant use with indomethacin capsules in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7)  Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7)  Digoxin: Concomitant use with indomethacin capsules can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) -------------------USE IN SPECIFIC POPULATIONS--------------------------- Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1) Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of indomethacin capsules in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. REVISED MAY 2016 INDO:R29mmh Reference ID: 3928097 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: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis 2.3 Acute painful shoulder (bursitis and/or tendinitis) 2.4 Acute Gouty Arthritis 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Premature Closure of Fetal Ductus Arteriosus 5.11 Hematologic Toxicity 5.12 Masking of Inflammation and Fever 5.13 Laboratory Monitoring 5.14 Central Nervous System Effects 5.15 Ocular Effects 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 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 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 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3928097 2 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: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)].  Indomethacin capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE Indomethacin capsules are indicated for:  Moderate to severe rheumatoid arthritis including acute flares of chronic disease.  Moderate to severe ankylosing spondylitis.  Moderate to severe osteoarthritis.  Acute painful shoulder (bursitis and/or tendinitis).  Acute gouty arthritis. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin capsules. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. Dosage Recommendations for Active Stages of the Following: Reference ID: 3928097 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis Indomethacin capsules 25 mg twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 mg to 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, indomethacin should be used with greater care in the elderly [see Use in Specific Populations (8.5)]. 2.3 Acute painful shoulder (bursitis and/or tendinitis) 75 mg to 150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7 to 14 days. 2.4. Acute gouty arthritis Indomethacin capsules 50 mg three times a day until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. 3 DOSAGE FORMS AND STRENGTHS Indomethacin capsules: The 25 mg capsules are hard-shell gelatin capsules with a light green opaque cap and a light green opaque body axially printed with MYLAN over 143 in black ink on both the cap and body. 4 CONTRAINDICATIONS Indomethacin capsules are contraindicated in the following patients: Reference ID: 3928097 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]  In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the Reference ID: 3928097 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of indomethacin capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients:  Use the lowest effective dosage for the shortest possible duration.  Avoid administration of more than one NSAID at a time.  Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.  Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.  If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue indomethacin capsules until a serious GI adverse event is ruled out.  In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Reference ID: 3928097 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue indomethacin capsules immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including indomethacin capsules, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of indomethacin capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If indomethacin capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver Reference ID: 3928097 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of indomethacin capsules in patients with advanced renal disease. The renal effects of indomethacin capsules may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating indomethacin capsules. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of indomethacin capsules [see Drug Interactions (7)]. Avoid the use of indomethacin capsules in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If indomethacin capsules are used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 5.7 Anaphylactic Reactions Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, indomethacin capsules are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When indomethacin capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Reference ID: 3928097 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.9 Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of indomethacin capsules at the first appearance of skin rash or any other sign of hypersensitivity. Indomethacin capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Premature Closure of Fetal Ductus Arteriosus Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including indomethacin capsules, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations (8.1)]. 5.11 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with indomethacin capsules have any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including indomethacin capsules, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.12 Masking of Inflammation and Fever The pharmacological activity of indomethacin capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.13 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.14 Central Nervous System Effects Indomethacin may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue indomethacin if severe CNS adverse reactions develop. Indomethacin may cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin. Reference ID: 3928097 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.15 Ocular Effects Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. Be alert to the possible association between the changes noted and indomethacin. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. Indomethacin is not indicated for long-term treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:  Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]  GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]  Hepatotoxicity [see Warnings and Precautions (5.3)]  Hypertension [see Warnings and Precautions (5.4)]  Heart Failure and Edema [see Warnings and Precautions (5.5)]  Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]  Anaphylactic Reactions [see Warnings and Precautions (5.7)]  Serious Skin Reactions [see Warnings and Precautions (5.9)]  Hematologic Toxicity [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving indomethacin capsules than in the group taking indomethacin suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with indomethacin suppositories or capsules was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for indomethacin capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely. Reference ID: 3928097 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1 Summary of Adverse Reactions for Indomethacin Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea * with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) CENTRAL NERVOUS SYSTEM headache (11.7%) anxiety (includes nervousness) light-headedness dizziness* muscle weakness syncope vertigo involuntary muscle movements paresthesia somnolence insomnia aggravation of epilepsy and depression and muzziness parkinsonism fatigue psychic disturbances including depersonalization (including malaise psychotic episodes coma and listlessness) mental confusion drowsiness peripheral neuropathy convulsion dysarthria SPECIAL SENSES tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin capsules blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC None edema weight gain hyperglycemia glycosuria Reference ID: 3928097 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Incidence greater than 1% Incidence less than 1% fluid retention flushing or sweating hyperkalemia INTEGUMENTARY none pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia * Reactions occurring in 3% to 9% of patients treated with indomethacin capsules. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal Relationship Unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely Reference ID: 3928097 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak. Genitourinary: urinary frequency A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A  hemolytic streptococcus, has been described in persons treated with nonsteroidal anti- inflammatory agents, including indomethacin, sometimes with fatal outcome. 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with indomethacin. Table 2: Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact:  Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.  Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin is not a substitute for low dose aspirin for cardiovascular protection. Reference ID: 3928097 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact:  NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).  In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention:  During concomitant use of indomethacin capsules and ACE inhibitors, ARBs, or beta blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.  During concomitant use of indomethacin capsules and ACE- inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].  When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [see Warnings and Precautions (5.6)]. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of Reference ID: 3928097 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda digoxin. Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between Reference ID: 3928097 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including indomethacin capsules, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including indomethacin capsules, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of indomethacin capsules in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies, retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. Reference ID: 3928097 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of indomethacin capsules during labor or delivery. In animal studies, NSAIDS, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Animal data Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 and 0.2 times the MRHD on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 Lactation Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin capsules and any potential adverse effects on the breastfed infant from the indomethacin capsules or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the Reference ID: 3928097 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including indomethacin capsules, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger have not been established. Indomethacin capsules should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin capsules. If a decision is made to use indomethacin for pediatric patients 2 years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1 to 2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150 to 200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150 to 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Indomethacin may cause confusion or, rarely, psychosis (see Adverse Reactions); physicians should remain alert to the possibility of such adverse effects in the elderly. Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Reference ID: 3928097 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology 12.3]. Because elderly patients are more likely to have decreased renal function 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800 222-1222). 11 DESCRIPTION Indomethacin Capsules, for oral administration are provided in one dosage strength which contain 25 mg of indomethacin. Indomethacin is a nonsteroidal anti-inflammatory indole derivative designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3 acetic acid with the following structural formula: structural formula C19H16ClNO4 M.W. 357.79 Reference ID: 3928097 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The molecular formula is C19H16ClNO4 and the molecular weight is 357.79. Indomethacin, USP is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. Each capsule for oral administration contains 25 mg of indomethacin and the following inactive ingredients: colloidal silicon dioxide, gelatin, FD&C Green No. 3, magnesium stearate, microcrystalline cellulose, powdered cellulose, sodium lauryl sulfate, sodium starch glycolate, titanium dioxide and D&C Yellow No. 10. The imprinting ink contains the following: black iron oxide, D&C Yellow No.10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, pharmaceutical glaze and propylene glycol. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of indomethacin capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption Following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Reference ID: 3928097 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elimination Metabolism Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dosage is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of indomethacin capsules have not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of indomethacin capsules have not been investigated in patients with hepatic impairment. Renal Impairment: The pharmacokinetics of indomethacin capsules have not been investigated in patients with renal impairment [see Warnings and Precautions (5.)]. Drug Interaction Studies: Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)]. When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no Reference ID: 3928097 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times and 0.07 times the MRHD on a mg/m2 basis, respectively). Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). 14 CLINICAL STUDIES Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long- term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease. Indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. 16 HOW SUPPLIED/STORAGE AND HANDLING Indomethacin Capsules, USP containing 25 mg of indomethacin, USP: The 25 mg capsule is a hard-shell gelatin capsule with a light green opaque cap and a light green opaque body axially printed with MYLAN over 143 in black ink on both the cap and body. The capsule is filled with a white powder blend. They are available as follows: NDC 0378-0143-01 bottles of 100 capsules NDC 0378-0143-10 bottles of 1000 capsules Storage and Handling Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.] Reference ID: 3928097 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin capsules and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin capsules and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions Advise patients to stop indomethacin capsules immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Reference ID: 3928097 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fetal Toxicity Inform pregnant women to avoid use of indomethacin capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of indomethacin capsules with other NSAIDs or salicylates(e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with indomethacin capsules until they talk to their healthcare provider [see Drug Interactions (7)]. company logo Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. REVISED MAY 2016 INDO:R29mmh Reference ID: 3928097 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including:  Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.  Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o longer use of NSAIDs o smoking o drinking alcohol o older age o poor health o advanced liver disease o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short- term pain. Who should not take NSAIDs? Do not take NSAIDs:  if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.  right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:  have liver or kidney problems  have high blood pressure  have asthma  are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 Reference ID: 3928097 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda weeks of pregnancy.  are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?  new or worse high blood pressure  heart failure  liver problems including liver failure  kidney problems including kidney failure  low red blood cells (anemia)  life-threatening skin reactions  life threatening allergic reactions  Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms:  shortness of breath or trouble breathing  chest pain  weakness in one part or side of your body  slurred speech  swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:  nausea  more tired or weaker than usual  diarrhea  itching  your skin or eyes look yellow  indigestion or stomach pain  flu-like symptoms  vomit blood  there is blood in your bowel movement or it is black and sticky like tar  unusual weight gain  skin rash or blisters with fever  swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs  Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.  Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Reference ID: 3928097 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO RX). This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. REVISED MAY 2016 INDO:R29mmh Reference ID: 3928097 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:59.648588	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018858s041s042lbl.pdf', 'application_number': 18858, 'submission_type': 'SUPPL ', 'submission_number': 41}
11,355	STERILE INDOCIN~I.V. (Indomethacin for Injection) Rx only No. 511 DESCRIPTION Sterile INDOCIN* LV. (Indomethacin for Injection) for intravenous administration is lyophilized indomethacin for injection. Each vial contains indomethacin for injection equivalent to 1 mg indomethacin as a white to yellow lyophilized powder or plug. Variations in the size of the lyophilized plug and the intensity of color have no relationship to the quality or amount of indomethacin present in the viaL. Indomethacin for injection is designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl- 1 H-indole-3-acetic acid, sodium salt, trihydrate. Its molecular weight is 433.82. Its empirical formula is C19H15CINNa0403H20 and its structural formula is: ~ I CH. ~. .3H"O CH,o . '" CH,i: CLINICAL PHARMACOLOGY Although the exact mechanism of action through which indomethacin causes closure of a patent ductus arteriosus is not known, it is believed to be through inhibition of prostaglandin synthesis. Indomethacin has been shown to be a potent inhibitor of prostaglandin synthesis, both in vitro and in vivo. In human newborns with certain congenital heart malformations, PGE 1 dilates the ductus arteriosus. In fetal and newborn lambs, E type prostaglandins have also been shown to maintain the patency of the ductus, and as in human newborns, indomethacin causes its constriction. Studies in healthy young animals and in premature infants with patent ductus arteriosus indicated that, after the first dose of intravenous indomethacin, there was a transient reduction in cerebral blood flow velocity and cerebral blood flow. Similar 'decreases in mesenteric blood flow and velocity have been observed. The clinical significance of these effects has not been established. In double-blind, placebo-controlled studies of INOOCIN LV. in 460 small pre-term infants, weighing 1750 g or less, the neonates treated with placebo had a ductus closure rate after 48 hours of 25 to 30 percent, whereas those treated with INOOCIN LV. had a 75 to 80 percent closure rate. In one of these studies, a multicenter study, involving 405 pre-term infants, later re- opening of the ductus arteriosus occurred in 26 percent of neonates treated with INOOCIN LV., however, 70 percent of these closed subsequently without the need for surgery or additional indomethacin. Pharmacokinetics and Metabolism The disposition of indomethacin following intravenous administration (0.2 mg/kg) in pre-term neonates with patent ductus arteriosus has not been extensively evaluated. Even though the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda plasma half-life of indomethacin was variable among premature infants, it was shown to vary inversely with postnatal age and weight. In one study, of 28 neonates who could be evaluated, the plasma half-life in those less than 7 days old averaged 20 hours (range: 3-60 hours, n=18). In neonates older than 7 days, the mean plasma half-life of indomethacin was 12 hours (range: 4-38 hours, n=10). Grouping the neonates by weight, mean plasma half-life in those weighing less than 1000 g was 21 hours (range: 9-60 hours, n=10); in those neonates weighing more than 1000 g, the mean plasma half-life was 15 hours (range: 3-52 hours, n=18). Following intravenous administration in adults, indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean plasma half-life of indomethacin is 4.5 hours. In the absence of enterohepatic circulation, it is 90 minutes. Indomethacin has been found to cross the blood-brain barrier and the placenta. In adults, about 99 percent of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. The percent bound in neonates has not been studied. In controlled trials in premature infants, however, no evidence of bilirubin displacement has been observed as evidenced by increased incidence of bilirubin encephalopathy (kernicterus). INDICATIONS AND USAGE INOOCIN LV. is indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1750 g when after 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support, etc.) is ineffective. Clear-cut clinical evidence of a hemodynamically significant patent ductus arteriosus should be present, such as respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly and pulmonary plethora on chest x-ray. CONTRAINDICATIONS INOOCIN LV. is contraindicated in: neonates with proven or suspected infection that is untreated; neonates who are bleeding, especially those with active intracranial hemorrhage or gastrointestinal bleeding; neonates with thrombocytopenia; neonates with coagulation defects; neonates with or who are suspected of having necrotizing enterocolitis; neonates with significant impairment of renal function; neonates with congenital heart disease in whom patency of the ductus arteriosus is necessary for satisfactory pulmonary or systemic blood flow (e.g., pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta). WARNINGS Gastrointestinal Effects: In the collaborative study, major gastrointestinal bleeding was no more common in those neonates receiving indomethacin than in those neonates on placebo. However, minor gastrointestinal bleeding (Le., chemical detection of blood in the stool) was more commonly noted in those neonates treated with indomethacin. Severe gastrointestinal effects have been reported in adults with various arthritic disorders treated chronically with oral indomethacin. (For further information, see package insert for Capsules INOOCIN* (Indomethacin).) Central Nervous System Effects: Prematurity per se, is associated with an increased incidence of spontaneous intraventricular hemorrhage. Because indomethacin may inhibit platelet aggregation, the potential for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda intraventricular bleeding may be increased. However, in the large multicenter study of INDOCIN LV. (see CLINICAL PHARMACOLOGY), the incidence of intraventricular hemorrhage in neonates treated with INDOCIN LV. was not significantly higher than in the control neonates. Renal Effects: INOOCIN LV. may cause significant reduction in urine output (50 percent or more) with concomitant elevations of blood urea nitrogen and creatinine, and reductions in glomerular filtration rate and creatinine clearance. These effects in most neonates are transient, disappearing with cessation of therapy with INDOCIN LV. However, because adequate renal function can depend upon renal prostaglandin synthesis, INDOCIN LV. may precipitate renal insufficiency, including acute renal failure, especially in neonates with other conditions that may adversely affect renal function (e.g., extracellular volume depletion from any cause, congestive heart failure, sepsis, concomitant use of any nephrotoxic drug, hepatic dysfunction). When significant suppression of urine volume occurs after a dose of INDOCIN LV., no additional dose should be given until the urine output returns to normal levels. INOOCIN LV. in pre-term infants may suppress water excretion to a greater extent than sodium excretion. When this occurs, a significant reduction in serum sodium values (Le., hyponatremia) may result. Neonates should have serum electrolyte determinations done during therapy with INOOCIN LV. Renal function and serum electrolytes should be monitored (see PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION). PRECAUTIONS General INOOCIN (Indomethacin) may mask the usual signs and symptoms of infection. Therefore, the physician must be continually on the alert for this and should use the drug with extra care in the presence of existing controlled infection. Severe hepatic reactions have been reported in adults treated chronically with oral indomethacin for arthritic disorders. (For further information, see package insert for Capsules INDOCIN (Indomethacin).) If clinical signs and symptoms consistent with liver disease develop in the neonate, or if systemic manifestations occur, INDOCIN LV. should be discontinued. INDOCIN LV. may inhibit platelet aggregation. In one small study, platelet aggregation was grossly abnormal after indomethacin therapy (given orally to premature infants to close the ductus arteriosus). Platelet aggregation returned to normal by the tenth day. Premature infants should be observed for signs of bleeding. The drug should be administered carefully to avoid extravascular injection or leakage as the solution may be irritating to tissue. Drug Interactions Since renal function may be reduced by INDOCIN LV., consideration should be given to reduction in dosage of those medications that rely on adequate renal function for their elimination. Because the half-life of digitalis (given frequently to pre-term infants with patent ductus arteriosus and associated cardiac failure) may be prolonged when given concomitantly with indomethacin, the neonate should be observed closely; frequent ECGs and serum digitalis levels may be required to prevent or detect digitalis toxicity early. Furthermore, in one study of premature infants treated with INDOCIN LV. and also receiving either gentamicin or amikacin, both peak and trough levels of these aminoglycosides were significantly elevated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Therapy with indomethacin may blunt the natriuretic effect of furosemide. This response has been attributed to inhibition of prostaglandin synthesis by non-steroidal anti-inflammatory drugs. In a study of 19 premature infants with patent ductus arteriosus treated with either INDOCIN LV. alone or a combination of INDOCIN LV. and furosemide, results showed that neonates receiving both INDOCIN LV. and furosemide had significantly higher urinary output, higher levels of sodium and chloride excretion, and higher glomerular filtration rates than did those receiving INDOCIN LV. alone. In this study, the data suggested that therapy with furosemide helped to maintain renal function in the premature infant when INDOCIN LV. was added to the treatment of patent ductus arteriosus. Indomethacin usually does not influence the hypoprothrombinemia produced by anticoagulants. When indomethacin is added to anticoagulants, prothrombin time should be monitored closely. In post marketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and INDOCIN LV. Caution should be exercised when INDOCIN LV. and anticoagulants are administered concomitantly. In some patients with compromised renal function, the co-administration of an NSAID and an ACE inhibitor or angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Neonatal Effects In rats and mice, oral indomethacin 4.0 mg/kg/day given during the last three days of gestation caused a decrease in maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses was observed. At 2.0 mg/kg/day, no increase in neuronal necrosis was observed as compared to the control groups. Administration of 0.5 or 4.0 mg/kg/day during the first three days of life did not cause an increase in neuronal necrosis at either dose leveL. Pregnant rats, given 2.0 mg/kg/day and 4.0 mg/kg/day during the last trimester of gestation, delivered offspring whose pulmonary blood vessels were both reduced in number and excessively muscularized. These findings are similar to those observed in the syndrome of persistent pulmonary hypertension of the neonate. ADVERSE REACTIONS In a double-blind, placebo-controlled trial of 405 premature infants weighing less than or equal to 1750 g with evidence of large ductal shunting, in those neonates treated with indomethacin (n=206), there was a statistically significantly greater incidence of bleeding problems, including gross or microscopic bleeding into the gastrointestinal tract, oozing from the skin after needle stick, pulmonary hemorrhage, and disseminated intravascular coagulopathy. There was no statistically significant difference between treatment groups with reference to intracranial hemorrhage. The neonates treated with indomethacin for injection also had a significantly higher incidence of transient oliguria and elevations of serum creatinine (greater than or equal to 1.8 mg/dL) than did the neonates treated with placebo. The incidences of retrolental fibroplasia (grades III and IV) and pneumothorax in neonates treated with INDOCIN LV. were no greater than in placebo controls and were statistically significantly lower than in surgically-treated neonates. The following additional adverse reactions in neonates have been reported from the collaborative study, anecdotal case reports, from other studies using rectal, oral, or intravenous indomethacin for treatment of patent ductus arteriosus or in marketed use. The rates are calculated from a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda database which contains experience of 849 indomethacin-treated neonates reported in the medical literature, regardless of the route of administration. One year follow-up is available on 175 neonates and shows no long-term sequelae which could be attributed to indomethacin. In controlled clinical studies, only electrolyte imbalance and renal dysfunction (of the reactions listed below) occurred statistically significantly more frequently after INDOCIN LV. than after placebo. Reactions marked with a single asterisk () occurred in 3-9 percent of indomethacin-treated neonates; those marked with a double asterisk () occurred in 3-9 percent of both indomethacin- and placebo-treated neonates. Unmarked reactions occurred in less than 3 percent of neonates. Renal: renal dysfunction in 41 percent of neonates, including one or more of the following: reduced urinary output; reduced urine sodium, chloride, or potassium, urine osmolality, free water clearance, or glomerular filtration rate; elevated serum creatinine or BUN; uremia. Cardiovascular. intracranial bleeding, pulmonary hypertension. Gastrointestinal: gastrointestinal bleeding, vomiting, abdominal distention, transient ileus, gastric perforation, localized perforation(s) of the small and/or large intestine, necrotizing enterocolitis. Metabolic: hyponatremia, elevated serum potassium, reduction in blood sugar, including hypoglycemia, increased weight gain (fluid retention). Coagulation: decreased platelet aggregation (see PRECAUTIONS). The following adverse reactions have also been reported in neonates treated with indomethacin, however, a causal relationship to therapy with INDOCIN LV. has not been established: Cardiovascular. bradycardia. Respiratory: apnea, exacerbation of pre-existing pulmonary infection. Metabolic: acidosis/alkalosis. Hematologic: disseminated intravascular coagulation. Ophthalmic: retrolental fibroplasia. ** A variety of additional adverse experiences have been reported in adults treated with oral indomethacin for moderate to severe rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute painful shoulder and acute gouty arthritis (see package insert for Capsules INDOCIN (Indomethacin) for additional information concerning adverse reactions and other cautionary statements). Their relevance to the pre-term infant receiving indomethacin for patent ductus arteriosus is unknown, however, the possibility exists that these experiences may be associated with the use of INDOCIN LV. in preterm infants. DOSAGE AND ADMINISTRATION FOR INTRAVENOUS ADMINISTRATION ONLY. Dosage recommendations for closure of the ductus arteriosus depend on the age of the infant at the time of therapy. A course of therapy is defined as three intravenous doses of INDOCIN LV. given at 12-24 hour intervals, with careful attention to urinary output. If anuria or marked oliguria (urinary output oeO.6 mL/kg/hr) is evident at the scheduled time of the second or third dose of INDOCIN LV., no additional doses should be given until laboratory studies indicate that renal function has returned to normal (see WARNINGS, Renal Effects). Dosage according to age is as follows: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda AGE at DOSAGE (mg/kg) 1 st dose Less than 1 st 2nd 3rd 48 hours 0.2 0.1 0.1 2-7 days 0.2 0.2 0.2 over 0.2 0.25 0.25 7 days If the ductus arteriosus closes or is significantly reduced in size after an interval of 48 hours or more from completion of the first course of INDOCIN LV., no further doses are necessary. If the ductus arteriosus re-opens, a second course of 1-3 doses may be given, each dose separated by a 12-24 hour interval as described above. If the neonate remains unresponsive to therapy with INDOCIN LV. after 2 courses, surgery may be necessary for closure of the ductus arteriosus. If severe adverse reactions occur, STOP THE DRUG. Directions For Use Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The reconstituted solution is clear, slightly yellow and essentially free from visible particles. The solution should be prepared onlv with 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection. Benzyl alcohol as a preservative has been associated with toxicity in neonates. Therefore, all diluents should be preservative-free. If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL. Any unused portion of the solution should be discarded because there is no preservative contained in the viaL. A fresh solution should be prepared just prior to each administration. Once reconstituted, the indomethacin solution may be injected intravenously. While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20-30 minutes. INDOCIN LV. is not buffered. Further dilution with intravenous infusion solutions is not recommended. HOW SUPPLIED Sterile INDOCIN LV. is a lyophilized white to yellow powder or plug supplied as single dose vials containing indomethacin for injection, equivalent to 1 mg indomethacin. NDC 67386-511-51. Storage Store below 30°C (86°F). Protect from light. Store container in carton unti contents have been used. Manufactured by Merck & Co. Inc., Whitehouse Station, NJ 08889, U.S.A for: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVATION Pharm:Bceuticals Deerfeld, IL60015, U.S.A Revised July 2006 Printed in USA *Registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, U.S.A TBD This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:59.827129	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018878s024lbl.pdf', 'application_number': 18878, 'submission_type': 'SUPPL ', 'submission_number': 24}
11,356	Figure 1: DELFLEX® Conventional with stay•safe® Exchange Set– 2.5% Dextrose, Low Mg/Low Ca Figure 2: DELFLEX® Conventional with stay•safe® Exchange Set – 4.25% Dextrose, Low Mg/Standard Ca Reference ID: 3683488 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 3: DELFLEX® Neutral pH with stay•safe® Exchange Set – 1.5% Dextrose, Low Mg/Low Ca Figure 4: DELFLEX® Neutral pH with stay•safe® Exchange Set – 2.5% Dextrose, Low Mg/Standard Ca Reference ID: 3683488 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 5: DELFLEX® Neutral pH with stay•safe® Exchange Set – 1.5% Dextrose, Standard Mg/Standard Ca Figure 6: DELFLEX® Conventional – 4.25% Dextrose, Low Mg/Low Ca Reference ID: 3683488 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 7: DELFLEX® Conventional – 2.5% Dextrose, Low Mg/Standard Ca Figure 8: DELFLEX® Conventional – 1.5% Dextrose, Standard Mg/Standard Ca Reference ID: 3683488 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 9: DELFLEX® Neutral pH – 1.5% Dextrose, Low Mg/Low Ca Figure 10: DELFLEX® Neutral pH – 1.5% Dextrose, Low Mg/Standard Ca Reference ID: 3683488 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 11: DELFLEX® Neutral pH – 4.25% Dextrose, Standard Mg/Standard Ca Reference ID: 3683488 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:44:59.924786	{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018883Orig1s057,020171Orig1s039lbl.pdf', 'application_number': 18883, 'submission_type': 'SUPPL ', 'submission_number': 57}
11,352	NS aspirin, SSRIs/SNRIs): HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INDOMETHACIN CAPSULES safely and effectively. See full prescribing information for INDOMETHACIN CAPSULES. Indomethacin Capsules, USP for oral use Initial U.S. Approval: 1965 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning.  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1)  Indomethacin Capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1)  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) RECENT MAJOR CHANGES Boxed Warning 05/2016 Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 05/2016 Warnings and Precautions, Heart Failure and Edema (5.5) 05/2016 INDICATIONS AND USAGE Indomethacin Capsules, USP are nonsteroidal anti-inflammatory drug indicated for (1)  Moderate to severe rheumatoid arthritis including acute flares of chronic disease  Moderate to severe ankylosing spondylitis  Moderate to severe osteoarthritis  Acute painful shoulder (bursitis and/or tendinitis)  Acute gouty arthritis DOSAGE AND ADMINISTRATION  Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1)  The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis is 25 mg two or three times a day (2.2)  The dosage for acute painful shoulder (bursitis and/or tendinitis) is 75-150 mg daily in 3 or 4 divided doses (2.3)  The dosage for acute gouty arthritis is 50 mg three times a day, until pain is tolerable (2.4) DOSAGE FORMS AND STRENGTHS Indomethacin Capsules: 25 mg and 50 mg (3) CONTRAINDICATIONS  Known hypersensitivity to indomethacin or any components of the drug product (4)  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4)  In the setting of CABG surgery (4) WARNINGS AND PRECAUTIONS Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3)  Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7)  Heart Failure and Edema: Avoid use of indomethacin capsules in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5)  Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of indomethacin capsules in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6)  Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7)  Exacerbation of Asthma Related to Aspirin Sensitivity: Indomethacin Capsules are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8)  Serious Skin Reactions: Discontinue indomethacin capsules at first appearance of skin rash or other signs of hypersensitivity (5.9)  Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30 weeks gestation (5.10, 8.1)  Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.11, 7) ADVERSE REACTIONS Most common adverse (incidence ≥ 3%) are headache, dizziness, dyspepsia, and nausea. (Error! Reference source not found..1) To report SUSPECTED ADVERSE REACTIONS, contact Heritage Pharmaceuticals Inc. at 1.866.901.DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIO  Drugs that Interfere with Hemostasis (e.g. warfarin, Monitor patients for bleeding who are concomitantly taking i ndomethacin capsules with drugs that interfere with hemostasis. Concomitant use of indomethacin and analgesic doses of aspirin is not generally recommended (7)  ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with indomethacin capsules may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7)  ACE Inhibitors and ARBs: Concomitant use with indomethacin capsules in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7)  Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7)  Digoxin: Concomitant use with indomethacin capsules can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7) USE IN SPECIFIC POPULATIONS Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1) Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of indomethacin capsules in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 05/2016 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1. INDICATIONS AND USAGE 2. DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis 2.3 Acute painful shoulder (bursitis and/or tendinitis) 2.4 Acute Gouty Arthritis 3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious Skin Reactions 5.10 Premature Closure of Fetal Ductus Arteriosus 5.11 Hematologic Toxicity 5.12 Masking of Inflammation and Fever 5.13 Laboratory Monitoring 5.14 Central Nervous System Effects 5.15 Ocular Effects 6. ADVERSE REACTIONS 6.1 Clinical Trials Experience 7. DRUG INTERACTIONS 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 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 14. CLINICAL STUDIES 16. HOW SUPPLIED/STORAGE AND HANDLING 17. PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3928099 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: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • Indomethacin Capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE Indomethacin Capsules are indicated for:  Moderate to severe rheumatoid arthritis including acute flares of chronic disease.  Moderate to severe ankylosing spondylitis.  Moderate to severe osteoarthritis.  Acute painful shoulder (bursitis and/or tendinitis).  Acute gouty arthritis. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin capsules. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. Dosage Recommendations for Active Stages of the Following: 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis Indomethacin Capsules 25 mg twice a day or three times daily. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 - 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug. Reference ID: 3928099 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 persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, indomethacin should be used with greater care in the elderly. [see Use in Specific Populations (8.5)] 2.3 Acute painful shoulder (bursitis and/or tendinitis) 75-150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7 14 days. 2.4 Acute Gouty Arthritis Indomethacin Capsules 50 mg three times a day, until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. 3 DOSAGE FORMS AND STRENGTHS Indomethacin capsules: The 25 mg capsule is a hard-shell gelatin capsule with an opaque pink cap and an opaque white body debossed with “HP/10” on both the body and cap. Indomethacin capsules: The 50 mg capsule is a hard-shell gelatin capsule with an opaque pink cap and an opaque white body debossed with “HP/11” on both the body and cap. 4 CONTRAINDICATIONS Indomethacin Capsules are contraindicated in the following patients:  Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]  In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] Reference ID: 3928099 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 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV- related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID- treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of indomethacin capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients:  Use the lowest effective dosage for the shortest possible duration.  Avoid administration of more than one NSAID at a time.  Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.  Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.  If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue indomethacin until a serious GI adverse event is ruled out.  In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue indomethacin immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including indomethacin capsules, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX- Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of indomethacin capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If indomethacin capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of indomethacin capsules in patients with advanced renal disease. The renal effects of indomethacin capsules may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating indomethacin capsules. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of indomethacin capsules [see Drug Interactions (7)]. Avoid the use of indomethacin capsules in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If indomethacin is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. 5.7 Anaphylactic Reactions Indomethacin has been associated with anaphylactic reactions in patients with and without known Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, indomethacin capsules are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When indomethacin capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of indomethacin capsules at the first appearance of skin rash or any other sign of hypersensitivity. Indomethacin capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Premature Closure of Fetal Ductus Arteriosus Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including indomethacin capsules, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations (8.1)]. 5.11 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with indomethacin capsules has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including indomethacin capsules, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.12 Masking of Inflammation and Fever The pharmacological activity of indomethacin capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.13 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 5.14 Central Nervous System Effects: Indomethacin may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. If severe CNS adverse reactions develop, indomethacin should be discontinued. Indomethacin may cause drowsiness; therefore, patients should be cautioned about engaging in Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin. 5.15 Ocular Effects: Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. The prescribing physician should be alert to the possible association between the changes noted and indomethacin. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients where therapy is prolonged. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:  Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]  GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]  Hepatotoxicity [see Warnings and Precautions (5.3)]  Hypertension [see Warnings and Precautions (5.4)]  Heart Failure and Edema [see Warnings and Precautions (5.5)]  Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]  Anaphylactic Reactions [see Warnings and Precautions (5.7)]  Serious Skin Reactions [see Warnings and Precautions (5.9)]  Hematologic Toxicity [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving indomethacin capsules than in the group taking indomethacin Suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with indomethacin Suppositories or Capsules was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for indomethacin capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely. Table 1: Summary of Adverse reactions for Indomethacin Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea* with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) Anorexia bloating (includes distension) flatulence gastrointestinal bleeding without obvious ulcer formation and Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda diarrhea abdominal distress or pain constipation peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness* vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES Tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None Hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC none Edema weight gain fluid retention flushing or sweating Hyperglycemia glycosuria hyperkalemia INTEGUMENTARY None Pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None Leucopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema Dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None Hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None Epistaxis breast changes, including enlargement and tenderness, or gynecomastia *Reactions occurring in 3% to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak. Genitourinary: Urinary frequency. A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome. 7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with indomethacin. Table 2: Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]. Aspirin Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [see Warnings and Precautions (5.6)]. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects.Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. Methotrexate Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including indomethacin capsules, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda indomethacin capsules, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of indomethacin capsules in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post- implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of indomethacin capsules during labor or delivery. In animal studies, NSAIDS, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Animal data Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times and 0.2 times the MRHD on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses, however, no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 Lactation Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin capsules and any potential adverse effects on the breastfed infant from the indomethacin capsules or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including indomethacin capsules, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. Indomethacin capsules should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin capsules. If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1 - 2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150 - 200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150 - 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Indomethacin may cause confusion or, rarely, psychosis [see Adverse Reaction (6)]; physicians should remain alert to the possibility of such adverse effects in the elderly. Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222 1222). 11 DESCRIPTION Indomethacin Capsules, USP is a nonsteroidal anti-inflammatory drug, available as 25 mg and 50 mg capsules for oral administration. The chemical name is1-(4-chlorobenzoyl)-5-methoxy-2 methyl-1H-indole-3-acetic acid. The molecular weight is 357.79. Its molecular formula is C19H16ClNO4, and it has the following chemical structure. structural formula Indomethacin is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The inactive ingredients in indomethacin capsules include: D & C Red #28, FD&C Blue #1, FD&C Red #3, gelatin, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, silicon dioxide, sodium lauryl sulfate, starch and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of indomethacin capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Elimination Metabolism: Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl desbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion: Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dosage is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of indomethacin capsules have not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of indomethacin capsules have not been investigated in patients with hepatic impairment. Renal Impairment: The pharmacokinetics of indomethacin capsules have not been investigated in patients with renal impairment [see Warnings and Precautions (Error! Reference source not found.)]. Drug Interaction Studies Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% (see Drug Interactions (Error! Reference source not found.). When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (Error! Reference source not found.)]. 13 NONCLINICAL TOXICOLOGY Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13.3 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the maximum recommended human daily dose [MRHD] on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times and 0.07 times the MRHD on a mg/m2 basis, respectively). Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethal in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis). 14 CLINICAL STUDIES Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease. Indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin m ay enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. 16 HOW SUPPLIED/STORAGE AND HANDLING Indomethacin Capsules are supplied containing 25 mg or 50 mg of indomethacin. The 25 mg capsule is a hard-shell gelatin capsule with an opaque pink cap and an opaque white body debossed with “HP/10” on both the body and cap. They are supplied in bottles of 100 and 1000 as follows: NDC 23155-010-01 bottles of 100 NDC 23155-010-10 bottles of 1000 The 50 mg capsule is a hard-shell gelatin capsule with an opaque pink cap and an opaque white body debossed with “HP/11” on both the body and cap. They are supplied in bottles of 100 and 500 as follows: NDC 23155-011-01 bottles of 100 NDC 23155-011-05 bottles of 500 Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Storage Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin capsules and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advice patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin capsules and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advice patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions Advice patients to stop indomethacin capsules immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of indomethacin capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of indomethacin capsules with other NSAIDs or salicylates Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with indomethacin capsules until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured for: Heritage Pharmaceuticals Inc. Eatontown, NJ 07724 1.866.901.DRUG (3784) PON/DRUGS/16 13 4193 Issued: 05/16 Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including:  Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.  Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs:  if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.  right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you:  have liver or kidney problems  have high blood pressure  have asthma  are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.  are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?  new or worse high blood pressure  heart failure  liver problems including liver failure  kidney problems including kidney failure  low red blood cells (anemia)  life-threatening skin reactions  life-threatening allergic reactions  Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: shortness of breath or trouble breathing slurred speech chest pain swelling of the face or throat weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: nausea  vomit blood more tired or weaker than usual  there is blood in your bowel movement or diarrhea it is black and sticky like tar itching  unusual weight gain your skin or eyes look yellow  skin rash or blisters with fever indigestion or stomach pain  swelling of the arms, legs, hands and flu-like symptoms feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Heritage Pharmaceuticals Inc. at 1.866.901.DRUG (3784). Other information about NSAIDs  Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.  Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Heritage Pharmaceuticals Inc. 12 Christopher Way, Suite 300, Eatontown, NJ 07724 For more information, go to www.heritagepharma.com or call 1.866.901.DRUG (3784) This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 05/16 Reference ID: 3928099 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:00.009306	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018851s025lbl.pdf', 'application_number': 18851, 'submission_type': 'SUPPL ', 'submission_number': 25}
11,357	Boehringer Ingelheim Catapres-TTS ® (clonidine) Catapres-TTS® -1 Catapres-TTS® -2 Catapres-TTS® -3 Transdermal Therapeutic System Programmed delivery in vivo of 0.1, 0.2, or 0.3 mg clonidine per day, for one week. Rx only Prescribing Information DESCRIPTION CATAPRES-TTS is a transdermal system providing continuous systemic delivery of clonidine for 7 days at an approximately constant rate. Clonidine is a centrally acting alpha-agonist hypotensive agent. It is an imidazoline derivative with the chemical name 2, 6-dichloro-N-2-imidazolidinylidenebenzenamine and has the following chemical structure: CATAPRES chemical structure of catapres-tts (clonidine) System Structure and Components CATAPRES-TTS transdermal therapeutic system is a multi-layered film, 0.2 mm thick, containing clonidine as the active agent. The system areas are 3.5 cm2 (CATAPRES-TTS-1), 7.0 cm2 (CATAPRES-TTS-2) and 10.5 cm2 (CATAPRES-TTS-3) and the amount of drug released is directly proportional to the area (see Release Rate Concept). The composition per unit area is the same for all three doses. Proceeding from the visible surface towards the surface attached to the skin, there are four consecutive layers: 1) a backing layer of pigmented polyester and aluminum film; 2) a drug reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide; 3) a microporous polypropylene membrane that controls the rate of delivery of clonidine from the system to the skin surface; 4) an adhesive formulation of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide. Prior to use, a protective slit release liner of polyester that covers the adhesive layer is removed. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cross Section of the System: Backing Drug Reservoir Control Membrane Adhesive Slit Release Liner Release Rate Concept Catapres-TTS® (clonidine) transdermal therapeutic system is programmed to release clonidine at an approximately constant rate for 7 days. The energy for drug release is derived from the concentration gradient existing between a saturated solution of drug in the system and the much lower concentration prevailing in the skin. Clonidine flows in the direction of the lower concentration at a constant rate, limited by the rate-controlling membrane, so long as a saturated solution is maintained in the drug reservoir. Following system application to intact skin, clonidine in the adhesive layer saturates the skin site below the system. Clonidine from the drug reservoir then begins to flow through the rate-controlling membrane and the adhesive layer of the system into the systemic circulation via the capillaries beneath the skin. Therapeutic plasma clonidine levels are achieved 2 to 3 days after initial application of CATAPRES-TTS transdermal therapeutic system. The 3.5, 7.0, and 10.5 cm2 systems deliver 0.1, 0.2, and 0.3 mg of clonidine per day, respectively. To ensure constant release of drug for 7 days, the total drug content of the system is higher than the total amount of drug delivered. Application of a new system to a fresh skin site at weekly intervals continuously maintains therapeutic plasma concentrations of clonidine. If the CATAPRES-TTS transdermal therapeutic system is removed and not replaced with a new system, therapeutic plasma clonidine levels will persist for about 8 hours and then decline slowly over several days. Over this time period, blood pressure returns gradually to pretreatment levels. 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. 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% - 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 responses 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 the release of growth hormone in children as well as adults but does not produce a chronic elevation of growth hormone with long-term use. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics The plasma half-life of clonidine is 12.7 ± 7 hours. Following oral administration, about 40-60% of the absorbed dose is recovered in the urine as unchanged drug within 24 hours. The remainder of the absorbed dose is metabolized in the liver. INDICATIONS AND USAGE Catapres-TTS® (clonidine) transdermal therapeutic system is indicated in the treatment of hypertension. It may be employed alone or concomitantly with other antihypertensive agents. CONTRAINDICATIONS CATAPRES-TTS transdermal therapeutic system should not be used in patients with known hypersensitivity to clonidine or to any other component of the therapeutic system. 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 confusion 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, 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-TTS transdermal therapeutic system 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-TTS transdermal therapeutic system. PRECAUTIONS General In patients who have developed localized contact sensitization to CATAPRES-TTS transdermal therapeutic system continuation of CATAPRES-TTS transdermal therapeutic system or substitution of oral clonidine hydrochloride therapy may be associated with development of a generalized skin rash. In patients who develop an allergic reaction to CATAPRES-TTS transdermal therapeutic system, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). CATAPRES-TTS transdermal therapeutic system should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease, or chronic renal failure. In rare instances, loss of blood pressure control has been reported in patients using CATAPRES-TTS transdermal therapeutic system according to the instructions for use. Perioperative Use CATAPRES-TTS transdermal therapeutic system therapy should not be interrupted during the surgical period. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. Physicians considering starting CATAPRES-TTS transdermal therapeutic system therapy during the perioperative period must be aware that therapeutic plasma clonidine levels are not achieved until 2 to 3 days after 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda initial application of Catapres-TTS® (clonidine) transdermal therapeutic system (see DOSAGE AND ADMINISTRATION). Defibrillation or Cardioversion The transdermal clonidine systems should be removed before attempting defibrillation or cardioversion because of the potential for altered electrical conductivity which may increase the risk of arcing, a phenomenon associated with the use of defibrillators. MRI Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because the CATAPRES-TTS PATCH contains aluminum, it is recommended to remove the system before undergoing an MRI. Information for Patients Patients should be cautioned against interruption of CATAPRES-TTS transdermal therapeutic system 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-TTS transdermal therapeutic system may cause dryness of eyes. Patients should be instructed to consult their physicians promptly about the possible need to remove the patch if they observe moderate to severe localized erythema and/or vesicle formation at the site of application or generalized skin rash. If a patient experiences isolated, mild localized skin irritation before completing 7 days of use, the system may be removed and replaced with a new system applied to a fresh skin site. If the system should begin to loosen from the skin after application, the patient should be instructed to place the adhesive cover directly over the system to ensure adhesion during its 7-day use. Used CATAPRES-TTS PATCHES contain a substantial amount of their initial drug content which may be harmful to infants and children if accidentally applied or ingested. THEREFORE, PATIENTS SHOULD BE CAUTIONED TO KEEP BOTH USED AND UNUSED CATAPRES-TTS PATCHES OUT OF THE REACH OF CHILDREN. After use, CATAPRES-TTS should be folded in half with the adhesive sides together and discarded away from children’s reach. Instructions for use, storage and disposal of the system are provided at the end of this monograph. These instructions are also included in each box of CATAPRES-TTS transdermal therapeutic system. Drug Interactions Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine 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. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 to 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 and female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times the 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) 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 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 is excreted in human milk, caution should be exercised when Catapres-TTS® (clonidine) transdermal therapeutic system is 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). 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Clinical trial experience with CATAPRES-TTS Most systemic adverse effects during Catapres-TTS® (clonidine) transdermal therapeutic system therapy have been mild and have tended to diminish with continued therapy. In a 3-month multi- clinic trial of CATAPRES-TTS transdermal therapeutic system in 101 hypertensive patients, the systemic adverse reactions were, dry mouth (25 patients) and drowsiness (12), fatigue (6), headache (5), lethargy and sedation (3 each), insomnia, dizziness, impotence/sexual dysfunction, dry throat (2 each) and constipation, nausea, change in taste and nervousness (1 each). In the above mentioned 3-month controlled clinical trial, as well as other uncontrolled clinical trials, the most frequent adverse reactions were dermatological and are described below. In the 3-month trial, 51 of the 101 patients had localized skin reactions such as erythema (26 patients) and/or pruritus, particularly after using an adhesive cover throughout the 7-day dosage interval. Allergic contact sensitization to CATAPRES-TTS transdermal therapeutic system was observed in 5 patients. Other skin reactions were localized vesiculation (7 patients), hyperpigmentation (5), edema (3), excoriation (3), burning (3), papules (1), throbbing (1), blanching (1), and a generalized macular rash (1). In additional clinical experience, contact dermatitis resulting in treatment discontinuation was observed in 128 of 673 patients (about 19 in 100) after a mean duration of treatment of 37 weeks. The incidence of contact dermatitis was about 34 in 100 among white women, about 18 in 100 in white men, about 14 in 100 in black women, and approximately 8 in 100 in black men. Analysis of skin reaction data showed that the risk of having to discontinue CATAPRES-TTS transdermal therapeutic system treatment because of contact dermatitis was greatest between treatment weeks 6 and 26, although sensitivity may develop either earlier or later in treatment. In a large-scale clinical acceptability and safety study by 451 physicians in a total of 3539 patients, other allergic reactions were recorded for which a causal relationship to CATAPRES-TTS transdermal therapeutic system was not established: maculopapular rash (10 cases); urticaria (2 cases); and angioedema of the face (2 cases), which also affected the tongue in one of the patients. Marketing Experience with CATAPRES-TTS The following adverse reactions have been identified during post-approval use of CATAPRES TTS transdermal therapeutic system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to CATAPRES-TTS transdermal therapeutic system. Body as a Whole: Fever; malaise; weakness; pallor; and withdrawal syndrome. Cardiovascular: Congestive heart failure; cerebrovascular accident; electrocardiographic abnormalities (i.e., bradycardia, sick sinus syndrome disturbances and arrhythmias); chest pain; orthostatic symptoms; syncope; increases in blood pressure; sinus bradycardia and atrioventricular (AV) block with and without the use of concomitant digitalis; Raynaud’s phenomenon; tachycardia; bradycardia; and palpitations. Central and Peripheral Nervous System/Psychiatric: Delirium; mental depression; hallucinations (including visual and auditory); localized numbness; vivid dreams or nightmares; restlessness; anxiety; agitation; irritability; other behavioral changes; and drowsiness. Dermatological: Angioneurotic edema; localized or generalized rash; hives; urticaria; contact dermatitis; pruritus; alopecia; and localized hypo or hyper pigmentation. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal: Anorexia and vomiting. Genitourinary: Difficult micturition; loss of libido; and decreased sexual activity. Metabolic: Gynecomastia or breast enlargement and weight gain. Musculoskeletal: Muscle or joint pain; and leg cramps. Ophthalmological: Blurred vision; burning of the eyes and dryness of the eyes. Adverse Events Associated with Oral CATAPRES Therapy: 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 (clonidine hydrochloride, USP) 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 AV 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 the eyes. OVERDOSAGE Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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. If symptoms of poisoning occur following dermal exposure, remove all Catapres-TTS® (clonidine) transdermal therapeutic systems. After their removal, the plasma clonidine levels will persist for about 8 hours, then decline slowly over a period of several days. Rare cases of CATAPRES-TTS poisoning due to accidental or deliberate mouthing or ingestion of the patch have been reported, many of them involving children. There is no specific antidote for clonidine overdosage. Ipecac syrup-induced vomiting and gastric lavage would not be expected to remove significant amounts of clonidine following dermal exposure. If the patch is ingested, whole bowel irrigation may be considered and the administration of activated charcoal and/or 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 Apply CATAPRES-TTS transdermal therapeutic system once every 7 days to a hairless area of intact skin on the upper outer arm or chest. Each new application of CATAPRES-TTS transdermal therapeutic system should be on a different skin site from the previous location. If the system loosens during 7-day wearing, the adhesive cover should be applied directly over the system to ensure good adhesion. There have been rare reports of the need for patch changes prior to 7 days to maintain blood pressure control. To initiate therapy, CATAPRES-TTS transdermal therapeutic system dosage should be titrated according to individual therapeutic requirements, starting with CATAPRES-TTS-1. If after one or two weeks the desired reduction in blood pressure is not achieved, increase the dosage by adding another CATAPRES-TTS-1 or changing to a larger system. An increase in dosage above two CATAPRES-TTS-3 is usually not associated with additional efficacy. When substituting CATAPRES-TTS transdermal therapeutic system for oral clonidine or for other antihypertensive drugs, physicians should be aware that the antihypertensive effect of CATAPRES-TTS transdermal therapeutic system may not commence until 2-3 days after initial application. Therefore, gradual reduction of prior drug dosage is advised. Some or all previous antihypertensive treatment may have to be continued, particularly in patients with more severe forms of hypertension. 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. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED CATAPRES-TTS-1, CATAPRES-TTS-2, and CATAPRES-TTS-3 are supplied as 4 pouched systems and 4 adhesive covers per carton. See chart below. Programmed Delivery Clonidine in vivo Per Day Over 1 Week Clonidine Size Code Content Catapres-TTS®-1 0.1 mg 2.5 mg 3.5 cm2 BI-31 (clonidine) NDC 0597-0031-34 Catapres-TTS®-2 0.2 mg 5.0 mg 7.0 cm2 BI-32 (clonidine) NDC 0597-0032-34 Catapres-TTS®-3 0.3 mg 7.5 mg 10.5 cm2 BI-33 (clonidine) NDC 0597-0033-34 STORAGE AND HANDLING Store below 86°F (30°C). Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Licensed from: Boehringer Ingelheim International GmbH Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY. ©Copyright 2009 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Rev: October 2009 IT7000DJ0709 4044415/07 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Boehringer Ingelheim PATIENT INSTRUCTIONS Catapres-TTS ® (clonidine) Transdermal Therapeutic System (Read the following instructions carefully before using this medication. If you have any questions, please consult with your doctor.) General Information CATAPRES-TTS transdermal therapeutic system is a square, tan adhesive PATCH containing an active blood-pressure-lowering medication. It is designed to deliver the drug into the body through the skin smoothly and consistently for one full week. Normal exposure to water, as in showering, bathing, and swimming, should not affect the PATCH. The optional white, round ADHESIVE COVER should be applied directly over the PATCH, should the PATCH begin to separate from the skin. The ADHESIVE COVER ensures that the PATCH sticks to the skin. The CATAPRES-TTS PATCH must be replaced with a new one on a fresh skin site if the one in use significantly loosens or falls off. patch placement on upper arm Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because the Catapres- TTS® PATCH contains aluminum, it is recommended to remove the system before undergoing an MRI. How to Apply the CATAPRES-TTS PATCH 1) Apply the square, tan CATAPRES-TTS PATCH once a week, preferably at a convenient time on the same day of the week (i.e., prior to bedtime on Tuesday of week one; prior to bedtime on Tuesday of week two, etc.). 2) Select a hairless area such as on the upper, outer arm or upper chest. The area chosen 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 pouches Figure2 should be free of cuts, abrasions, irritation, scars or calluses and should not be shaved before applying the Catapres-TTS® (clonidine) PATCH. Do not place the CATAPRES-TTS PATCH on skin folds or under tight undergarments, since premature loosening may occur. 3) Wash hands with soap and water and thoroughly dry them. 4) Clean the area chosen with soap and water. Rinse and wipe dry with a clean, dry tissue. 5) Select the pouch with the red and orange colors labeled CATAPRES-TTS (clonidine) and open it as illustrated in Figure 3. Remove the square, tan PATCH from the pouch. opening pouch Figure 3 6) Remove the clear plastic protective backing from the PATCH by gently peeling off one half of the backing at a time as shown in Figure 4. Avoid touching the sticky side of the Catapres-TTS® (clonidine) PATCH. removing clar plastic protective backing Figure 4 7) Place the CATAPRES-TTS PATCH on the prepared skin site (sticky side down) by applying firm pressure over the PATCH to ensure good contact with the skin, especially around the 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda edges (Figure 5). Discard the clear plastic protective backing and wash your hands with soap and water to remove any drug from your hands. hand near upper arm Figure 5 8) After one week, remove the old PATCH and discard it (refer to Instructions for Disposal). After choosing a different skin site, repeat instructions 2 through 7 for the application of your next CATAPRES-TTS PATCH. What to do if your CATAPRES-TTS PATCH becomes loose while wearing: How to Apply the ADHESIVE COVER Note: The white, round, ADHESIVE COVER does not contain any drug and should not be used alone. The COVER should be applied directly over the CATAPRES-TTS PATCH only if the PATCH begins to separate from the skin, thereby ensuring that it sticks to the skin for seven full days. pouch and patch Figure 6 1) Wash hands with soap and water and thoroughly dry them. 2) Using a clean, dry tissue, make sure that the area around the square, tan Catapres-TTS® (clonidine) PATCH is clean and dry. Press gently on the CATAPRES-TTS PATCH to ensure that the edges are in good contact with the skin. 3) Take the white, round, ADHESIVE COVER (Figure 6) from the plain white pouch and remove the paper liner backing from the COVER. 4) Carefully center the round, white ADHESIVE COVER over the square, tan 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CATAPRES-TTS PATCH and apply firm pressure, especially around the edges in contact with the skin. Instructions for Disposal KEEP OUT OF REACH OF CHILDREN During or even after use, a PATCH contains active medication which may be harmful to infants and children if accidentally applied or ingested. After use, fold in half with the sticky sides together. Dispose of carefully out of reach of children. Manufactured by: ALZA Corporation Mountain View, CA 94043 USA Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Licensed from: Boehringer Ingelheim International GmbH ©Copyright 2009 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Rev: March October 2009 IT7000DCJC073099 4044415/076 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:00.346464	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018891s025lbl.pdf', 'application_number': 18891, 'submission_type': 'SUPPL ', 'submission_number': 25}
11,359	Intravenous Solutions Rx only with Heparin Sodium Injection 12,500 or 25,000 USP Units of Heparin Sodium in 0.45% Sodium Chloride Injection Flexible Plastic Container DESCRIPTION Intravenous solutions with heparin sodium (derived from porcine intestinal mucosa) are sterile, nonpyrogenic fluids for intravenous administration. They contain no bacteriostat or antimicrobial agent or added buffer. Edetate disodium, anhydrous is added as a stabilizer. The solution may contain sodium hydroxide and/or hydrochloric acid for pH adjustment. See Table for summary of contents and characteristics of these solutions. Heparin Sodium, USP is a heterogenous 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. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Structure of Heparin Sodium (representative subunits): structural formula Sodium Chloride, USP is chemically designated NaCl, a white crystalline compound freely soluble in water. Water for Injection, USP is chemically designated H2O. The flexible plastic container is fabricated from a specially formulated polyvinyl chloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out certain of its chemical components in very small amounts before the expiration period is attained. However, the safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers. 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 EN-2898 Page 1 of 9 Reference ID: 3063487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 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 in 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 site of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t ½ = 10') 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. Hypotonic concentrations of sodium chloride are suited for parenteral maintenance of water requirements when only small quantities of salt are desired. Sodium chloride in water dissociates to provide sodium (Na+) and chloride (Cl¯) ions. Sodium (Na+) is the principal cation of the extracellular fluid and plays a large part in the therapy of fluid and electrolyte disturbances. Chloride (Cl¯) has an integral role in buffering action when oxygen and carbon dioxide exchange occurs in the red blood cells. The distribution and excretion of sodium (Na+) are largely under the control of the kidney which maintains a balance between intake and output. 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. INDICATIONS AND USAGE Heparin sodium is indicated for: Atrial fibrillation with embolization; Treatment of acute and chronic consumption coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and heart surgery; Prophylaxis and treatment of peripheral arterial embolism; As an anticoagulant in extracorporeal circulation, and dialysis procedures. EN-2898 Page 2 of 9 Reference ID: 3063487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Heparin sodium should not be used in patients: With severe thrombocytopenia; In whom 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); With 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. 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 discontinued promptly (see OVERDOSAGE). Thrombocytopenia: Thrombocytopenia in patients receiving heparin has been reported at frequencies up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy. Obtain platelet counts before and periodically during heparin therapy. Monitor thrombocytopenia of any degree closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant (see Heparin- induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis). Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis: 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 known 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. Monitor thrombocytopenia of any degree Reference ID: 3063487 EN-2898 Page 3 of 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT and HITT 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. Solutions containing sodium ions 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 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. In patients with diminished renal function, administration of solutions containing sodium ions may result in sodium retention. Excessive administration of potassium-free solutions may result in significant hypokalemia. As the dosage of solutions of heparin sodium must be titrated to individual patient response, additive medications should not be delivered via this solution. PRECAUTIONS General: a. Heparin Resistance: Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. b. 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 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. Drug/Laboratory Test 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 EN-2898 Page 4 of 9 Reference ID: 3063487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, rises 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: 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. 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: Due to its large molecular weight, heparin is not likely to be excreted in human milk, and any heparin in milk would not be orally absorbed by a nursing infant. Exercise caution when administering Heparin Sodium to a nursing mother. 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). 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. EN-2898 Page 5 of 9 Reference ID: 3063487 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 site 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. 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 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 ½ 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, the labeling of Protamine Sulfate Injection, USP products should be consulted. In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS and PRECAUTIONS. EN-2898 Page 6 of 9 Reference ID: 3063487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Heparin sodium is not effective by oral administration and these premixed formulations should be given by intermittent intravenous injection or intravenous infusion. 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 the normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. 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. 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 Frequency Recommended Dose* Intermittent Intravenous Injection Initial Dose 10,000 Units, either undiluted or in 50 – 100 mL of 0.45% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 – 10,000 Units, either undiluted or in 50 – 100 mL of 0.45% Sodium Chloride Injection, USP Continuous Intravenous Infusion Initial Dose Continuous 5,000 Units by IV injection 20,000 – 40,000 Units/24 hours in 0.45% Sodium Chloride Injection, USP *Based on 150 lb. (68 kg) patient. 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) EN-2898 Page 7 of 9 Reference ID: 3063487 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. Extracorporeal Dialysis: Follow equipment manufacturer’s operating directions carefully. 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. (See PRECAUTIONS.) Do not administer unless the solution is clear and seal is intact. Discard unused portion. INSTRUCTIONS FOR USE To Open Tear outer wrap at notch 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. Preparation for Administration (Use aseptic technique) 1. Close flow control clamp of administration set. 2. Remove cover from outlet port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: See full directions on administration set carton. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber. 6. Open flow control clamp and clear air from set. Close clamp. 7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. 8. Regulate rate of administration with flow control clamp. WARNING: DO NOT USE FLEXIBLE CONTAINER IN SERIES CONNECTIONS. HOW SUPPLIED Intravenous solutions with heparin sodium are supplied in single-dose flexible plastic containers in varied sizes and concentrations as shown in the accompanying Table. EN-2898 Page 8 of 9 Reference ID: 3063487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Content and Characteristics Per 100 mL Per 1000 mL Heparin Edetate Sodium Heparin Sodium Disodium Osmolarity (Units/ Sodium Chloride (anhydrous) Sodium Chloride mOsmol/L pH Solution NDC No. Product mL) (Units) (grams) (mg) Na+ Cl¯ Tonicity (calc.) (range) Volume 0409-7650-62 Heparin 100 10,000 0.45 10 77 mEq 77 mEq Hypotonic 155 6.1 250 mL Sodium (5.0 - 7.5) 25,000 USP Units in 0.45% Sodium Chloride Injection 0409-7651-62 Heparin 50 5,000 0.45 10 77 mEq 77 mEq Hypotonic 155 6.1 250 mL Sodium (5.0 - 7.5) 12,500 USP Units in 0.45% Sodium Chloride Injection 0409-7651-03 Heparin 50 5,000 0.45 10 77 mEq 77 mEq Hypotonic 155 6.1 500 mL Sodium (5.0 - 7.5) 25,000 USP Units in 0.45% Sodium Chloride Injection Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. Revised: 09/2011 Printed in USA EN-2898 Hospira, Inc., Lake Forest, IL 60045 USA company logo EN-2898 Page 9 of 9 Reference ID: 3063487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:00.426834	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018916s057lbl.pdf', 'application_number': 18916, 'submission_type': 'SUPPL ', 'submission_number': 57}
11,360	Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 2912664 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:00.470218	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018917s025lbl.pdf', 'application_number': 18917, 'submission_type': 'SUPPL ', 'submission_number': 25}
11,358	company logo Catapres-TTS ® (clonidine) Catapres-TTS® -1 Catapres-TTS® -2 Catapres-TTS® -3 Transdermal Therapeutic System Programmed delivery in vivo of 0.1, 0.2, or 0.3 mg clonidine per day, for one week. Rx only Prescribing Information DESCRIPTION CATAPRES-TTS® (clonidine) is a transdermal system providing continuous systemic delivery of clonidine for 7 days at an approximately constant rate. Clonidine is a centrally acting alpha-agonist hypotensive agent. It is an imidazoline derivative with the chemical name 2, 6-dichloro-N-2-imidazolidinylidenebenzenamine and has the following chemical structure: CATAPRES structural formula (clonidine) System Structure and Components CATAPRES-TTS transdermal therapeutic system is a multi-layered film, 0.2 mm thick, containing clonidine as the active agent. The system areas are 3.5 cm2 (CATAPRES-TTS-1), 7.0 cm2 (CATAPRES-TTS-2) and 10.5 cm2 (CATAPRES-TTS-3) and the amount of drug released is directly proportional to the area (see Release Rate Concept). The composition per unit area is the same for all three doses. Proceeding from the visible surface towards the surface attached to the skin, there are four consecutive layers: 1) a backing layer of pigmented polyester and aluminum film; 2) a drug reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide; 3) a microporous polypropylene membrane that controls the rate of delivery of clonidine from the system to the skin surface; 4) an adhesive formulation of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide. Prior to use, a protective slit release liner of polyester that covers the adhesive layer is removed. 1 Reference ID: 3138575 Cross Section of the System: Backing Drug Reservoir Control Membrane Adhesive Slit Release Liner Release Rate Concept Catapres-TTS® (clonidine) transdermal therapeutic system is programmed to release clonidine at an approximately constant rate for 7 days. The energy for drug release is derived from the concentration gradient existing between a saturated solution of drug in the system and the much lower concentration prevailing in the skin. Clonidine flows in the direction of the lower concentration at a constant rate, limited by the rate-controlling membrane, so long as a saturated solution is maintained in the drug reservoir. Following system application to intact skin, clonidine in the adhesive layer saturates the skin site below the system. Clonidine from the drug reservoir then begins to flow through the rate-controlling membrane and the adhesive layer of the system into the systemic circulation via the capillaries beneath the skin. Therapeutic plasma clonidine levels are achieved 2 to 3 days after initial application of CATAPRES-TTS transdermal therapeutic system. The 3.5, 7.0, and 10.5 cm2 systems deliver 0.1, 0.2, and 0.3 mg of clonidine per day, respectively. To ensure constant release of drug for 7 days, the total drug content of the system is higher than the total amount of drug delivered. Application of a new system to a fresh skin site at weekly intervals continuously maintains therapeutic plasma concentrations of clonidine. If the CATAPRES-TTS transdermal therapeutic system is removed and not replaced with a new system, therapeutic plasma clonidine levels will persist for about 8 hours and then decline slowly over several days. Over this time period, blood pressure returns gradually to pretreatment levels. 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. 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 responses 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 the release of growth hormone in children as well as adults but does not produce a chronic elevation of growth hormone with long-term use. 2 Reference ID: 3138575 Pharmacokinetics Catapres-TTS® (clonidine) transdermal therapeutic system delivers clonidine at an approximately constant rate for 7 days. The absolute bioavailability of clonidine from the Catapres-TTS transdermal therapeutic system dosage form is approximately 60%. Steady-state clonidine plasma levels are obtained within 3 days after transdermal application to the upper outer arm and increase linearly with increasing size of the transdermal patch. Mean steady-state plasma concentrations with the 3.5 cm2, 7.0 cm2 and 10.5 cm2 systems are approximately 0.4 ng/mL, 0.8 ng/mL, and 1.1 ng/mL, respectively. Similar clonidine steady-state concentrations are reached after application to the chest. Steady-state clonidine plasma levels remain constant after removal of one system and application of a new system of the same size. 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 has a total clearance of 177 mL/min and a renal clearance of 102 mL/min. The apparent volume of distribution (Vz) of clonidine is 197 L (2.9 L/kg). 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 within 24 hours. About 50% of the absorbed dose is metabolized in the liver. After removal of the Catapres-TTS transdermal therapeutic system, clonidine plasma concentrations decline slowly with a half-life of approximately 20 hours. INDICATIONS AND USAGE Catapres-TTS transdermal therapeutic system is indicated in the treatment of hypertension. It may be employed alone or concomitantly with other antihypertensive agents. CONTRAINDICATIONS CATAPRES-TTS transdermal therapeutic system should not be used in patients with known hypersensitivity to clonidine or to any other component of the therapeutic system. 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, tremor, and confusion 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, 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-TTS transdermal therapeutic system 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-TTS transdermal therapeutic system. PRECAUTIONS General In patients who have developed localized contact sensitization to CATAPRES-TTS® (clonidine) transdermal therapeutic system continuation of CATAPRES-TTS transdermal therapeutic system 3 Reference ID: 3138575 or substitution of oral clonidine hydrochloride therapy may be associated with development of a generalized skin rash. In patients who develop an allergic reaction to CATAPRES-TTS transdermal therapeutic system, 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. In hypertension caused by pheochromocytoma, no therapeutic effect of CATAPRES-TTS transdermal therapeutic system can be expected. In rare instances, loss of blood pressure control has been reported in patients using CATAPRES-TTS transdermal therapeutic system according to the instructions for use. Perioperative Use CATAPRES-TTS transdermal therapeutic system therapy should not be interrupted during the surgical period. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. Physicians considering starting CATAPRES-TTS transdermal therapeutic system therapy during the perioperative period must be aware that therapeutic plasma clonidine levels are not achieved until 2 to 3 days after initial application of Catapres-TTS transdermal therapeutic system (see DOSAGE AND ADMINISTRATION). Defibrillation or Cardioversion The transdermal clonidine systems should be removed before attempting defibrillation or cardioversion because of the potential for altered electrical conductivity which may increase the risk of arcing, a phenomenon associated with the use of defibrillators. MRI Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because the CATAPRES-TTS PATCH contains aluminum, it is recommended to remove the system before undergoing an MRI. Information for Patients Patients should be cautioned against interruption of CATAPRES-TTS transdermal therapeutic system 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-TTS® (clonidine) transdermal therapeutic system may cause dryness of eyes. Patients should be instructed to consult their physicians promptly about the possible need to remove the patch if they observe moderate to severe localized erythema and/or vesicle formation at the site of application or generalized skin rash. 4 Reference ID: 3138575 If a patient experiences isolated, mild localized skin irritation before completing 7 days of use, the system may be removed and replaced with a new system applied to a fresh skin site. If the system should begin to loosen from the skin after application, the patient should be instructed to place the adhesive cover directly over the system to ensure adhesion during its 7-day use. Used CATAPRES-TTS PATCHES contain a substantial amount of their initial drug content which may be harmful to infants and children if accidentally applied or ingested. THEREFORE, PATIENTS SHOULD BE CAUTIONED TO KEEP BOTH USED AND UNUSED CATAPRES-TTS PATCHES OUT OF THE REACH OF CHILDREN. After use, CATAPRES-TTS should be folded in half with the adhesive sides together and discarded away from children’s reach. Instructions for use, storage and disposal of the system are provided at the end of this monograph. These instructions are also included in each box of CATAPRES-TTS transdermal therapeutic system. Drug Interactions Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine 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). 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 to 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 and female rats was unaffected by clonidine doses as high as 150 µg/kg (approximately 3 times the MRDHD). In a separate experiment, fertility of female rats appeared 5 Reference ID: 3138575 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) 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 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 As clonidine is excreted in human milk, caution should be exercised when Catapres-TTS® (clonidine) transdermal therapeutic system is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established in adequate and well- controlled trials. ADVERSE REACTIONS Clinical trial experience with CATAPRES-TTS Most systemic adverse effects during Catapres-TTS transdermal therapeutic system therapy have been mild and have tended to diminish with continued therapy. In a 3-month multi-clinic trial of CATAPRES-TTS transdermal therapeutic system in 101 hypertensive patients, the systemic adverse reactions were, dry mouth (25 patients) and drowsiness (12), fatigue (6), headache (5), lethargy and sedation (3 each), insomnia, dizziness, impotence/sexual dysfunction, dry throat (2 each) and constipation, nausea, change in taste and nervousness (1 each). In the above mentioned 3-month controlled clinical trial, as well as other uncontrolled clinical trials, the most frequent adverse reactions were dermatological and are described below. In the 3-month trial, 51 of the 101 patients had localized skin reactions such as erythema (26 patients) and/or pruritus, particularly after using an adhesive cover throughout the 7-day dosage interval. Allergic contact sensitization to CATAPRES-TTS transdermal therapeutic system was observed in 5 patients. Other skin reactions were localized vesiculation (7 patients), hyperpigmentation (5), edema (3), excoriation (3), burning (3), papules (1), throbbing (1), blanching (1), and a generalized macular rash (1). In additional clinical experience, contact dermatitis resulting in treatment discontinuation was observed in 128 of 673 patients (about 19 in 100) after a mean duration of treatment of 37 weeks. The incidence of contact dermatitis was about 34 in 100 among white women, about 18 in 100 in white men, about 14 in 100 in black women, and approximately 8 in 100 in black men. Analysis of skin reaction data showed that the risk of having to discontinue CATAPRES-TTS® (clonidine) transdermal therapeutic system treatment because of contact dermatitis was greatest between treatment weeks 6 and 26, although sensitivity may develop either earlier or later in treatment. 6 Reference ID: 3138575 In a large-scale clinical acceptability and safety study by 451 physicians in a total of 3539 patients, other allergic reactions were recorded for which a causal relationship to CATAPRES-TTS transdermal therapeutic system was not established: maculopapular rash (10 cases); urticaria (2 cases); and angioedema of the face (2 cases), which also affected the tongue in one of the patients. Marketing Experience with CATAPRES-TTS The following adverse reactions have been identified during post-approval use of CATAPRES TTS transdermal therapeutic system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to CATAPRES-TTS transdermal therapeutic system. Body as a Whole: Fever; malaise; weakness; pallor; and withdrawal syndrome. Cardiovascular: Congestive heart failure; cerebrovascular accident; electrocardiographic abnormalities (i.e., bradycardia, sick sinus syndrome disturbances and arrhythmias); chest pain; orthostatic symptoms; syncope; increases in blood pressure; sinus bradycardia and AV block with and without the use of concomitant digitalis; Raynaud’s phenomenon; tachycardia; bradycardia; and palpitations. Central and Peripheral Nervous System/Psychiatric: Delirium; mental depression; hallucinations (including visual and auditory); localized numbness; vivid dreams or nightmares; restlessness; anxiety; agitation; irritability; other behavioral changes; and drowsiness. Dermatological: Angioneurotic edema; localized or generalized rash; hives; urticaria; contact dermatitis; pruritus; alopecia; and localized hypo or hyper pigmentation. Gastrointestinal: Anorexia and vomiting. Genitourinary: Difficult micturition; loss of libido; and decreased sexual activity. Metabolic: Gynecomastia or breast enlargement and weight gain. Musculoskeletal: Muscle or joint pain; and leg cramps. Ophthalmological: Blurred vision; burning of the eyes and dryness of the eyes. Adverse Events Associated with Oral CATAPRES Therapy: 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® (clonidine hydrochloride, USP) 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 AV block have been reported, both with and without the use of concomitant digitalis. 7 Reference ID: 3138575 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 the 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. If symptoms of poisoning occur following dermal exposure, remove all Catapres-TTS® (clonidine) transdermal therapeutic systems. After their removal, the plasma clonidine levels will persist for about 8 hours, then decline slowly over a period of several days. Rare cases of CATAPRES-TTS poisoning due to accidental or deliberate mouthing or ingestion of the patch have been reported, many of them involving children. There is no specific antidote for clonidine overdosage. Ipecac syrup-induced vomiting and gastric lavage would not be expected to remove significant amounts of clonidine following dermal exposure. If the patch is ingested, whole bowel irrigation may be considered and the administration of activated charcoal and/or 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 8 Reference ID: 3138575 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 Apply CATAPRES-TTS® (clonidine) transdermal therapeutic system once every 7 days to a hairless area of intact skin on the upper outer arm or chest. Each new application of CATAPRES-TTS transdermal therapeutic system should be on a different skin site from the previous location. If the system loosens during 7-day wearing, the adhesive cover should be applied directly over the system to ensure good adhesion. There have been rare reports of the need for patch changes prior to 7 days to maintain blood pressure control. To initiate therapy, CATAPRES-TTS transdermal therapeutic system dosage should be titrated according to individual therapeutic requirements, starting with CATAPRES-TTS-1. If after one or two weeks the desired reduction in blood pressure is not achieved, increase the dosage by adding another CATAPRES-TTS-1 or changing to a larger system. An increase in dosage above two CATAPRES-TTS-3 is usually not associated with additional efficacy. When substituting CATAPRES-TTS transdermal therapeutic system for oral clonidine or for other antihypertensive drugs, physicians should be aware that the antihypertensive effect of CATAPRES-TTS transdermal therapeutic system may not commence until 2-3 days after initial application. Therefore, gradual reduction of prior drug dosage is advised. Some or all previous antihypertensive treatment may have to be continued, particularly in patients with more severe forms of hypertension. 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-TTS-1, CATAPRES-TTS-2, and CATAPRES-TTS-3 are supplied as 4 pouched systems and 4 adhesive covers per carton. See chart below. Programmed Delivery Clonidine in vivo Per Day Over 1 Week Clonidine Size Code Content Catapres-TTS®-1 0.1 mg 2.5 mg 3.5 cm2 BI-31 (clonidine) NDC 0597-0031-34 Catapres-TTS®-2 0.2 mg 5.0 mg 7.0 cm2 BI-32 (clonidine) NDC 0597-0032-34 Catapres-TTS®-3 0.3 mg 7.5 mg 10.5 cm2 BI-33 (clonidine) NDC 0597-0033-34 STORAGE AND HANDLING Store below 86°F (30°C). Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA 9 Reference ID: 3138575 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 IT7000GJ122011 4044415/09 10 Reference ID: 3138575 company logo PATIENT INSTRUCTIONS Catapres-TTS ® (clonidine) Transdermal Therapeutic System (Read the following instructions carefully before using this medication. If you have any questions, please consult with your doctor.) General Information Catapres-TTS® (clonidine) transdermal therapeutic system is a square, tan adhesive PATCH containing an active blood-pressure-lowering medication. It is designed to deliver the drug into the body through the skin smoothly and consistently for one full week. Normal exposure to water, as in showering, bathing, and swimming, should not affect the PATCH. The optional white, round ADHESIVE COVER should be applied directly over the PATCH, should the PATCH begin to separate from the skin. The ADHESIVE COVER ensures that the PATCH sticks to the skin. The CATAPRES-TTS PATCH must be replaced with a new one on a fresh skin site if the one in use significantly loosens or falls off. usage illustration Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because the CATAPRES-TTS PATCH contains aluminum, it is recommended to remove the system before undergoing an MRI. How to Apply the CATAPRES-TTS PATCH 1) Apply the square, tan CATAPRES-TTS PATCH once a week, preferably at a convenient time on the same day of the week (i.e., prior to bedtime on Tuesday of week one; prior to bedtime on Tuesday of week two, etc.). 2) Select a hairless area such as on the upper, outer arm or upper chest. The area chosen 11 Reference ID: 3138575 usage illustration Figure2 should be free of cuts, abrasions, irritation, scars or calluses and should not be shaved before applying the Catapres-TTS® (clonidine) PATCH. Do not place the CATAPRES-TTS PATCH on skin folds or under tight undergarments, since premature loosening may occur. 3) Wash hands with soap and water and thoroughly dry them. 4) Clean the area chosen with soap and water. Rinse and wipe dry with a clean, dry tissue. 5) Select the pouch with the red and orange colors labeled CATAPRES-TTS (clonidine) and open it as illustrated in Figure 3. Remove the square, tan PATCH from the pouch. usage illustration Figure 3 6) Remove the clear plastic protective backing from the PATCH by gently peeling off one half of the backing at a time as shown in Figure 4. Avoid touching the sticky side of the Catapres-TTS PATCH. usage illustration Figure 4 7) Place the CATAPRES-TTS PATCH on the prepared skin site (sticky side down) by applying firm pressure over the PATCH to ensure good contact with the skin, especially around the 12 Reference ID: 3138575 edges (Figure 5). Discard the clear plastic protective backing and wash your hands with soap and water to remove any drug from your hands. usage illustration Figure 5 8) After one week, remove the old PATCH and discard it (refer to Instructions for Disposal). After choosing a different skin site, repeat instructions 2 through 7 for the application of your next Catapres-TTS® (clonidine) PATCH. What to do if your CATAPRES-TTS PATCH becomes loose while wearing: How to Apply the ADHESIVE COVER Note: The white, round, ADHESIVE COVER does not contain any drug and should not be used alone. The COVER should be applied directly over the CATAPRES-TTS PATCH only if the PATCH begins to separate from the skin, thereby ensuring that it sticks to the skin for seven full days. Figure 6 1) Wash hands with soap and water and thoroughly dry them. 2) Using a clean, dry tissue, make sure that the area around the square, tan CATAPRES-TTS PATCH is clean and dry. Press gently on the CATAPRES-TTS PATCH to ensure that the edges are in good contact with the skin. 3) Take the white, round, ADHESIVE COVER (Figure 6) from the plain white pouch and remove the paper liner backing from the COVER. 4) Carefully center the round, white ADHESIVE COVER over the square, tan 13 Reference ID: 3138575 Catapres-TTS® (clonidine) PATCH and apply firm pressure, especially around the edges in contact with the skin. Instructions for Disposal KEEP OUT OF REACH OF CHILDREN During or even after use, a PATCH contains active medication which may be harmful to infants and children if accidentally applied or ingested. After use, fold in half with the sticky sides together. Dispose of carefully out of reach of children. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Licensed from: Boehringer Ingelheim International GmbH Copyright 2011 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Revised: October 2011 IT7000GJ122011 4044415/09 14 Reference ID: 3138575	custom-source	2025-02-12T13:45:00.540645	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018891s028lbl.pdf', 'application_number': 18891, 'submission_type': 'SUPPL ', 'submission_number': 28}
11,361	07-19-75-231 Baxter Lactated Ringer’s Irrigation in ARTHROMATIC Plastic Container DESCRIPTION Lactated Ringer’s Irrigation is a sterile, nonpyrogenic, isotonic solution in a single dose ARTHROMATIC plastic container for use as an arthroscopic irrigating solution. Each liter contains 6.0 g Sodium Chloride, USP, (NaCl), 3.1 g Sodium Lactate (C3H5NaO3), 300 mg Potassium Chloride, USP, (KCl), and 200 mg Calcium Chloride, USP, (CaCl2•2H2O). pH 6.5 (6.0 to 7.5). Milliequivalents per liter: Sodium - 130, Potassium 4, Calcium - 3, Chloride - 109, Lactate - 28. Osmolarity 273 mOsmol/L (calc.). No antimicrobial agent has been added. The ARTHROMATIC 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 ethylhexylphthalate (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 Irrigation is useful as an irrigating fluid for body joints because it approximates the electrolyte composition of synovial fluid, and provides a transparent fluid medium with optical properties suitable for good visualization of the interior joint surface during endoscopic examination. During arthroscopic surgical procedures, the solution acts as a lavage for removing blood, tissue fragments, and bone fragments. INDICATIONS AND USAGE Lactated Ringer’s Irrigation is indicated for use as an arthroscopic irrigating fluid with endoscopic instruments during arthroscopic procedures requiring distension and irrigation of the knee, shoulder, elbow, or other bone joints. 1 Reference ID: 3826517 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Lactated Ringer’s Irrigation is contraindicated in patients with a known hypersensitivity to Sodium Lactate. WARNINGS Absorption of large volume of irrigation fluids through a perforation or open wound may result in circulatory overload, cardiac failure, or electrolyte disturbances and acid-base imbalance. Patients and fluid balance should be monitored accordingly. If absorption of clinically relevant amounts of fluid is suspected, the fluid administration should be interrupted, and the patient evaluated for possible adverse consequences. Particularly close monitoring is required in patients with: • Severely impaired renal function • Impaired cardiac function, or • Clinical states in which there is edema with sodium retention as a fluid overload syndrome may develop in these patients following absorption of even small quantities of irrigation fluid. Appropriate therapy should be initiated, as indicated. Lactated Ringer’s Irrigation must not be used when types of electrocautery are used that are not safe and effective when performed in the presence of electrolyte solutions. Excessive volume or pressure during irrigation may cause excessive fluid absorption, undue distention of cavities, and/or disruption of tissue. PRECAUTIONS The container must not be vented. Vented administration sets with the vent in the open position should not be used with flexible plastic containers. Use of a vented administration set with the vent in the open position could result in air embolism. Pressurizing 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. 2 Reference ID: 3826517 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Drug Interactions If clinically relevant amounts of solution have been absorbed, potential interactions with other agents must be considered, such as: Patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids and carbenoxolone, may have an increased risk of sodium and fluid retention. Due to the alkalinizing action of lactate (formation of bicarbonate), Lactated Ringer’s Irrigation may interfere with the elimination of drugs for which renal elimination is pH dependent: • Renal clearance of acidic drugs such as salicylates, barbiturates, and lithium may be increased. • Renal clearance of alkaline drugs, such as sympathomimetics (e.g., ephedrine, pseudoephedrine), dextroamphetamine (dexamphetamine) sulfate, and fenfluramine (phenfluramine) hydrochloride may be decreased. The risk of hyperkalemia is increased in patients treated with agents or products that can cause hyperkalemia or increase the risk of hyperkalemia, such as potassium-sparing diuretics (amiloride, spironolactone, triameterene), 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. Absorption of calcium-containing solutions may increase the effects of digitalis and lead to serious or fatal cardiac arrhythmia. In patients treated with thiazide diuretics or vitamin D, the risk of hypercalcemia is increased. Pregnancy Teratogenic Effects 3 Reference ID: 3826517 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s Irrigation. It is also not known whether Lactated Ringer’s Irrigation can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s Irrigation should be given to a pregnant woman only if clearly needed. Nursing Mothers There is no adequate data from the use of Lactated Ringer’s Irrigation in lactating women. Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing Lactated Ringer’s Irrigation. Pediatric Use Safety and effectiveness in pediatric patients have not been established by adequate and well-controlled trials. Geriatric Use When selecting the type of irrigation solution and the volume, duration of irrigation, and pressure for a geriatric patient, consider that geriatric patients are more likely to have cardiac, renal, hepatic, and other diseases or concomitant drug therapy. ADVERSE REACTIONS Post-Marketing Adverse Reactions No adverse reactions were identified in Baxter’s Adverse Event Reporting System database with Lactated Ringer’s Irrigation. Class Reactions Adverse reactions reported with Lactated Ringer’s Irrigation (manufacturer unspecified) are: Fluid absorption manifested by Pulmonary edema, Edema, and Electrolyte disturbances. Though not indicated for intravenous administration, absorption of irrigation fluid into tissue or vasculature through a perforation or open wound is possible. As a result, adverse reactions reported with Lactated Ringer’s solutions with and without Dextrose for intravenous administration may be applicable and include: 4 Reference ID: 3826517 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Hypersensitivity reactions, including Anaphylactic/Anaphylactoid reactions, with 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, Headache, Hyperkalemia • Pyrexia Overdose In the event of clinically relevant absorption of irrigation fluid, the patients must be evaluated and corrective measures instituted as appropriate. DOSAGE AND ADMINISTRATION The volume and/or rate of solution needed will vary with the nature and duration of the arthroscopic procedure. This solution, as it is packaged, is not intended for IV administration or injection. The container must not be vented (See Precautions). 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. If particulate matter or discoloration is found, contact Baxter Customer Service Aseptic technique should be used when applying this product. The contents of an opened container should be used promptly to minimize the possibility of bacterial growth or pyrogen formation. Discard the unused portion of irrigating solution since no antimicrobial agent has been added. When using Lactated Ringer’s Irrigation for pour irrigation, prevent contact of the fluid with the external surface of the container. Lactated Ringer’s Irrigation is for single-patient use only. Microwave heating of irrigation fluids is not recommended. If desired, Lactated Ringer’s Irrigation may be warmed in a water bath or oven to not more than 45° C while 5 Reference ID: 3826517 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda maintaining sterility. Lactated Ringer’s Irrigation that has been warmed must not be returned to storage. Cetriaxone must not be mixed with calcium-containing solutions, including Lactated Ringer’s Irrigation. Additives may be incompatible with Lactated Ringer’s Irrigation. Additives known or determined to be incompatible should not be used. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for, for example, 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 Irrigation is appropriate. The instructions for use of the medication to be added and other relevant literature must be consulted. When making additions to Lactated Ringer’s Irrigation, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. HOW SUPPLIED Lactated Ringer’s Irrigation in ARTHROMATIC Plastic Container is available as follows: 2B7487 3000 mL NDC 0338-0137-27 2B7489 5000 mL NDC 0338-0137-29 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 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 6 Reference ID: 3826517 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing bag firmly. If leaks are found, discard solution as sterility may be impaired. Use Aseptic Technique. 1. Suspend container using hanger hole. 2. Remove protector from outlet port. 3. Attach irrigation set. Refer to complete directions accompanying set. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *Bar Code Position Only 071975-231 07-19-75-231 Revised September 2015 Baxter, ARTHROMATIC and PL 146 are trademarks of Baxter International Inc. 7 Reference ID: 3826517 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:00.699895	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018921s031lbl.pdf', 'application_number': 18921, 'submission_type': 'SUPPL ', 'submission_number': 31}
11,363	CALAN® (verapamil hydrochloride) For Intravenous Injection DESCRIPTION CALAN (verapamil HCl) is a calcium antagonist or slow-channel inhibitor available as a sterile solution for intravenous injection in 5-mg (2 ml) ampules, 5-mg (2 ml) and 10-mg (4 ml) syringes, and 5-mg (2 ml) and 10-mg (4 ml) vials. Each form contains verapamil HCl 2.5 mg/ml and sodium chloride 8.5 mg/ml in water for injection. Hydrochloric acid and/or sodium hydroxide is used for pH adjustment. The pH of the solution is between 4.1 and 6.0. The structural formula of verapamil HCl is given below: structural formula C27H38N2O4 · HCl M.W. = 491.08 Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]propyl]-3,4-dimethoxy α-(1-methylethyl) hydrochloride Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform, and methanol. Verapamil HCl is not chemically related to other antiarrhythmic drugs. CLINICAL PHARMACOLOGY Mechanism of action: CALAN inhibits the calcium ion (and possibly sodium ion) influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells. The antiarrhythmic effect of CALAN appears to be due to its effect on the slow channel in cells of the cardiac conductile system. Electrical activity through the SA and AV nodes depends, to a significant degree, upon calcium influx through the slow channel. By inhibiting this influx, CALAN slows AV conduction and prolongs the effective refractory period within the AV node in a rate-related manner. This effect results in a reduction of the ventricular rate in patients with atrial flutter and/or atrial fibrillation and a rapid ventricular response. By interrupting reentry at the AV node, CALAN can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardias (PSVT), including Wolff-Parkinson-White (WPW) syndrome. CALAN has no effect on conduction across accessory bypass tracts. CALAN does not alter the normal atrial action potential or intraventricular conduction time but depresses amplitude, velocity of depolarization, and conduction in depressed atrial fibers. Reference ID: 3038068 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In the isolated rabbit heart, concentrations of CALAN that markedly affect SA nodal fibers or fibers in the upper and middle regions of the AV node have very little effect on fibers in the lower AV node (NH region) and no effect on atrial action potentials or His bundle fibers. CALAN does not induce peripheral arterial spasm. CALAN has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. CALAN does not alter total serum calcium levels. Hemodynamics: CALAN reduces afterload and myocardial contractility. In most patients, including those with organic cardiac disease, the negative inotropic action of CALAN is countered by reduction of afterload, and cardiac index is usually not reduced, but in patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Peak therapeutic effects occur within 3 to 5 minutes after a bolus injection. The commonly used intravenous doses of 5-10 mg CALAN produce transient, usually asymptomatic, reduction in normal systemic arterial pressure, systemic vascular resistance and contractility; left ventricular filling pressure is slightly increased. Pharmacokinetics: Intravenously administered CALAN has been shown to be rapidly metabolized. Following intravenous infusion in man, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about 4 minutes) and a slower terminal elimination phase (half-life 2-5 hours). In healthy men, orally administered CALAN undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N- and O-dealkylated products of CALAN. Approximately 70% of an administered dose is excreted in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted as unchanged drug. INDICATIONS AND USAGE CALAN is indicated for the treatment of supraventricular tachyarrhythmias, including: • Rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, including those associated with accessory bypass tracts (Wolff-Parkinson-White [WPW] and Lown-Ganong-Levine [LGL] syndromes). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver) should be attempted prior to CALAN administration. • Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation, except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts (Wolff-Parkinson-White [WPW] and Lown-Ganong-Levine [LGL] syndromes). In controlled studies in the U.S., about 60% of patients with supraventricular tachycardia converted to normal sinus rhythm within 10 minutes after intravenous verapamil HCl. Uncontrolled studies reported in the world literature describe a conversion rate of about 80%. About 70% of patients with atrial flutter and/or fibrillation with a fast ventricular rate respond with a decrease in heart rate of at least 20%. Conversion of atrial flutter or fibrillation to sinus Reference ID: 3038068 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda rhythm is uncommon (about 10%) after verapamil HCl and may reflect the spontaneous conversion rate, since the conversion rate after placebo was similar. The effect of a single injection lasts for 30–60 minutes when conversion to sinus rhythm does not occur. Because a small fraction (<1.0%) of patients treated with verapamil HCl respond with life- threatening adverse responses (rapid ventricular rate in atrial flutter/fibrillation with an accessory bypass tract, marked hypotension, or extreme bradycardia/asystole–—see Contraindications and Warnings), the initial use of intravenous verapamil HCl should, if possible, be in a treatment setting with monitoring and resuscitation facilities, including DC-cardioversion capability (see Suggested Treatment of Acute Cardiovascular Adverse Reactions). As familiarity with the patient’s response is gained, an office setting may be acceptable. Cardioversion has been used safely and effectively after intravenous CALAN. CONTRAINDICATIONS Intravenous verapamil HCl is contraindicated in: 1. Severe hypotension or cardiogenic shock 2. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker) 3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4. Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy) 5. Patients receiving intravenous beta-adrenergic blocking drugs (e.g., propranolol). Intravenous verapamil and intravenous beta-adrenergic blocking drugs should not be administered in close proximity to each other (within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction. 6. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff- Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil is administered. 7. Ventricular tachycardia. Administration of intravenous verapamil to patients with wide- complex ventricular tachycardia (QRS≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting. 8. Known hypersensitivity to verapamil HCl WARNINGS CALAN SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME. (See Dosage and Administration.) Hypotension: Intravenous verapamil often produces a decrease in blood pressure below baseline levels that is usually transient and asymptomatic but may result in dizziness. Systolic pressure less than 90 mm Hg and/or diastolic pressure less than 60 mm Hg was seen in 5%-10% of patients in controlled U.S. trials in supraventricular tachycardia and in about 10% of the Reference ID: 3038068 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients with atrial flutter/fibrillation. The incidence of symptomatic hypotension observed in studies conducted in the U.S. was approximately 1.5%. Three of the five symptomatic patients required pharmacologic treatment (norepinephrine bitartrate IV, metaraminol bitartrate IV, or 10% calcium gluconate IV). All recovered without sequelae. Extreme bradycardia/asystole: Verapamil affects the AV and SA nodes and rarely may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients. Bradycardia associated with sick sinus syndrome was reported in 0.3% of the patients treated in controlled double-blind trials in the U.S. The total incidence of bradycardia (ventricular rate less than 60 beats/min) was 1.2% in these studies. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately. (See Adverse Reactions including suggested treatment of adverse reactions.) Heart failure: When heart failure is not severe or rate related, it should be controlled with digitalis glycosides and diuretics, as appropriate, before CALAN is used. In patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Concomitant antiarrhythmic therapy: Digitalis: Intravenous verapamil has been used concomitantly with digitalis preparations without the occurrence of serious adverse effects. However, since both drugs slow AV conduction, patients should be monitored for AV block or excessive bradycardia. Procainamide: Intravenous verapamil has been administered to a small number of patients receiving oral procainamide without the occurrence of serious adverse effects. Quinidine: Intravenous verapamil has been administered to a small number of patients receiving oral quinidine without the occurrence of serious adverse effects. However a few cases of hypotension have been reported in patients taking oral quinidine who received intravenous verapamil. Caution should therefore be used when employing this combination of drugs. Beta-adrenergic blocking drugs: Intravenous verapamil has been administered to patients receiving oral beta blockers without the development of serious adverse effects. However, since both drugs may depress myocardial contractility or AV conduction, the possibility of detrimental interactions should be considered. The concomitant administration of intravenous beta blockers and intravenous verapamil has resulted in serious adverse reactions (see Contraindications), especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction. Reference ID: 3038068 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Disopyramide: Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Heart block: CALAN prolongs AV conduction time. While high-degree AV block has not been observed in controlled clinical trials in the U.S., a low percentage (less than 0.5%) has been reported in the world literature. Development of second- or third-degree AV block or unifascicular, bifascicular, or trifascicular bundle branch block requires reduction in subsequent doses or discontinuation of verapamil and institution of appropriate therapy, if needed. (See Adverse Reactions and Concomitant antiarrhythmic therapy.) Hepatic and renal failure: Significant hepatic and renal failure should not increase the effects of a single intravenous dose of CALAN but may prolong its duration. Repeated injections of intravenous CALAN in such patients may lead to accumulation and an excessive pharmacologic effect of the drug. There is no experience to guide use of multiple doses in such patients, and this generally should be avoided. If repeated injections are essential, blood pressure and PR interval should be closely monitored and smaller repeat doses should be utilized. Data on the clearance of verapamil by dialysis are not yet available. Premature ventricular contractions: During conversion to normal sinus rhythm or marked reduction in ventricular rate, a few benign complexes of unusual appearance (sometimes resembling premature ventricular contractions) may be seen after treatment with verapamil. Similar complexes are seen during spontaneous conversion of supraventricular tachycardia and after DC-cardioversion or other pharmacologic therapy. These complexes appear to have no clinical significance. Duchenne’s muscular dystrophy: Intravenous verapamil can precipitate respiratory muscle failure in these patients and should, therefore, be used with caution. Increased intracranial pressure: Intravenous verapamil has been seen to increase intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction. Caution should be taken and appropriate monitoring performed. PRECAUTIONS Drug interactions: (See Warnings: Concomitant antiarrhythmic therapy.) Intravenous verapamil has been used concomitantly with other cardioactive drugs (e.g., digitalis) without evidence of serious negative drug interactions. In rare instances, including when patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly with intravenous verapamil, serious adverse effects have occurred. Concomitant use of verapamil with agents that decrease adrenergic function may result in an exaggerated hypotensive response. Animal studies suggest concomitant use of intravenous verapamil and intravenous dantrolene sodium may result in cardiovascular collapse. The clinical relevance of these findings is unknown. Reference ID: 3038068 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cimetidine has no effect on intravenous CALAN kinetics. As verapamil is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein- bound drugs. Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression. Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Telithromycin: Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class. Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine. HMG‐CoA reductase inhibitors: The use of HMG‐CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. Co‐administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5‐fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs. Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. 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. Labor and delivery: There have been few controlled studies to determine whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite Reference ID: 3038068 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda a long history of use of intravenous CALAN in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing mothers: Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Also, verapamil is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. Pediatric use: Controlled studies with verapamil have not been conducted in pediatric patients, but uncontrolled experience with intravenous administration in more than 250 patients, about half under 12 months of age and about 25% newborn, indicates that results of treatment are similar to those in adults. However, in rare instances, severe hemodynamic side effects have occurred following the intravenous administration of verapamil in neonates and infants. Caution should therefore be used when administering verapamil to this group of pediatric patients. The most commonly used single doses in patients up to 12 months of age have ranged from 0.1 to 0.2 mg/kg of body weight, while in patients aged 1 to 15 years, the most commonly used single doses ranged from 0.1 to 0.3 mg/kg of body weight. Most of the patients received the lower dose of 0.1 mg/kg once, but in some cases, the dose was repeated once or twice every 10 to 30 minutes. ADVERSE REACTIONS The following reactions were reported with intravenous verapamil use in controlled U.S. clinical trials involving 324 patients: Cardiovascular: Symptomatic hypotension (1.5%); bradycardia (1.2%); severe tachycardia (1.0%). The worldwide experience in open clinical trials in more than 7,900 patients was similar. Central nervous system effects: Dizziness (1.2%); headache (1.2%). Although rare, cases of seizures during verapamil injection has been reported. Gastrointestinal: Nausea (0.9%); abdominal discomfort (0.6%). In rare cases of hypersensitivity, broncho/laryngeal spasm accompanied by itch and urticaria has been reported. The following reactions were reported in a few patients: emotional depression, rotary nystagmus, sleepiness, vertigo, muscle fatigue, or diaphoresis. Suggested Treatment of Acute Cardiovascular Adverse Reactions* The frequency of these adverse reactions was quite low, and experience with their treatment has been limited. Adverse Proven Effective Supportive Reaction Treatment Treatment Reference ID: 3038068 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1. Symptomatic Dopamine HCl IV Intravenous hypotenstion Calcium chloride IV fluids requiring Norepinephrine bitartrate IV Trendelenburg treatment Metaraminol bitartrate IV position Isoproterenol HCl IV 2. Bradycardia, AV Isoproterenol HCl IV Intravenous block, Asystole Calcium chloride IV fluids Norepinephrine bitartrate IV (slow drip) Atropine sulfate IV Cardiac pacing 3. Rapid ventricular DC-cardioversion Intravenous rate (due to (high energy may fluids antegrade con- be required) (slow drip) duction in Procainamide IV flutter/fibrilla- Lidocaine HCl IV tion with WPW or LGL syndromes) *Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. OVERDOSAGE Treatment of overdosage should be supportive and individualized. Beta-adrenergic stimulation and/or parenteral administration of calcium solutions (calcium chloride) have been effectively used in treatment of deliberate overdosage with oral verapamil. Clinically significant hypotensive reactions or high-degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including isoproterenol hydrochloride, other vasopressor agents, or cardiopulmonary resuscitation (see Suggested Treatment of Acute Cardiovascular Adverse Reactions). DOSAGE AND ADMINISTRATION For intravenous use only. CALAN SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME UNDER CONTINUOUS ECG AND BLOOD PRESSURE MONITORING. The recommended intravenous doses of CALAN are as follows: Adult: Initial dose—5-10 mg (0.075-0.15 mg/kg body weight) given as an intravenous bolus. Repeat dose—10 mg (0.15 mg/kg body weight) 30 minutes after the first dose if the initial response is not adequate. Older patients—The dose should be administered over at least 3 minutes to minimize the risk of untoward drug effects. Pediatric: Initial dose 0-1 year: 0.1-0.2 mg/kg body weight (usual single dose range: 0.75-2 mg) should be administered as an intravenous bolus. 1-15 years: 0.1-0.3 mg/kg body weight (usual single dose range: 2-5 mg) should be Reference ID: 3038068 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administered as an intravenous bolus. Do not exceed 5 mg. Repeat dose 0-1 year: 0.1-0.2 mg/kg body weight (usual single dose range: 0.75-2 mg) 30 minutes after the first dose if the initial response is not adequate. 1-15 years: 0.1-0.3 mg/kg body weight (usual single dose range: 2-5 mg) 30 minutes after the first dose if the initial response is not adequate. Do not exceed 10 mg as a single dose. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and vial seal is intact. Unused amount of solution should be discarded immediately following withdrawal of any portion of contents. For stability reasons this product is not recommended for dilution with Sodium Lactate Injection USP in polyvinyl chloride bags. Admixing intravenous CALAN with albumin, amphotericin B, hydralazine HCl, and trimethoprim with sulfamethoxazole should be avoided. CALAN will precipitate in any solution with a pH above 6.0. HOW SUPPLIED All forms are individually packaged. Size NDC Number Carton Size 5-mg (2 ml) ampule 5-mg (2 ml) vial 10-mg (4 ml) vial 5-mg (2 ml) syringe 10-mg (4 ml) syringe 0025-1853-10 0025-1864-05 0025-1874-05 0025-1958-05 0025-1968-05 10 5 5 5 5 Store at 59° to 86°F (15° to 30°C) and protect from light during storage. company logo LAB-0421-2.0 Revised October 2011 Reference ID: 3038068 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:02.098293	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018925s008lbl.pdf', 'application_number': 18925, 'submission_type': 'SUPPL ', 'submission_number': 8}
11,365	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 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. 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 4 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 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 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. Co-administration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of carbamazepine with nefazodone is contraindicated. WARNINGS Patients with a history of adverse hematologic reaction to any drug may be particularly at risk. Severe dermatologic reactions, including toxic epidermal necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, have been reported with Tegretol. These reactions have been extremely rare. However, a few fatalities have been reported. 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 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 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. 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 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. 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 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 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, 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 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). Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. 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. 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 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 (see boxed WARNING), the skin, 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: Pruritic and erythematous rashes, urticaria, toxic epidermal necrolysis (Lyell’s syndrome) (see WARNINGS), Stevens-Johnson syndrome (see WARNINGS), 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, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 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. 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 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 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 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). 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 16 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 NDA 16-608/SLR-096; NDA 18-281/S-044; NDA18-927/S-035; NDA 20-234/S-025 Page 2 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 Inc. Whitby Operations Whitby Ontario, Canada L1N 5Z5 Tegretol XR Tablets Manufactured by: Novartis Pharma GmbH D-79664 Wehr, Germany Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 REV: July 2007 © 2007Novartis 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 8/16/2007 05:01:49 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:02.233415	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016608s096,018281s044,018927s035,020234s025REVISED_LABEL.pdf', 'application_number': 18927, 'submission_type': 'SUPPL ', 'submission_number': 35}
11,362	NDA 18-922/S-021 Page 3 Lodine (etodolac capsules 200 and 300 mg, and etodolac tablets 400 and 500 mg) ] only DescriptionDESCRIPTION Lodine (etodolac capsules and tablets) is a member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each tablet and capsule contains etodolac for oral administration. Etodolac is a racemic mixture of [+]S and [-]R-enantiomers. Etodolac is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. chemically designated as (±) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4- b]indole-1-acetic acid. The structural formula for etodolac is shown below: The chemical name is (±) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid. The molecular weight of the base is 287.37. It has a pKa of 4.65 and an n-octanol:water partition coefficient of 11.4 at pH 7.4. The molecular formula for etodolac is C17H21NO3, and it has the following structural formula: The empirical formula for etodolac is C17H21NO3. The molecular weight of the base is 287.37. It has a pKa of 4.65 and an n-octanol:water partition coefficient of 11.4 at pH 7.4. Etodolac is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. Inactive ingredients are: The inactive ingredients in Lodine include: in capsules: cellulose, gelatin, iron oxides, lactose, magnesium stearate, povidone, sodium lauryl sulfate, sodium starch glycolate, and titanium dioxide. in tablets: cellulose, hydroxypropyl methylcellulosehypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sodium starch glycolate, and titanium dioxide. The 400 mg tablets contain D&C Yellow #10, FD&C Blue #2, and FD&C Yellow #6 as color additives. The 500 mg tablets contain FD&C Blue #2 only. Lodine is available in 200 and 300 mg capsules, and 400 and 500 mg tablets, for oral administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 4 Clinical PharmacologyCLINICAL PHARMACOLOGY PHARMACOLOGYPharmacodynamics EtodolacLodine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolacLodine, like that of other NSAIDs, is not knowncompletely understood, but is believed to be associated with the inhibition ofmay be related to prostaglandin biosynthesissynthetase inhibition. Lodine is a racemic mixture of [-]R- and [+]S-etodolac. As with other NSAIDs, it has been demonstrated in animals that the [+]S-form is biologically active. Both enantiomers are stable and there is no [-]R to [+]S conversion in vivo. PHARMACODYNAMICS Analgesia was demonstrable 1/2 hour following single doses of 200 to 400 mg Lodine, with the peak effect occurring in 1 to 2 hours. The analgesic effect generally lasted for 4 to 6 hours (see Clinical Trials). PHARMACOKINETICSPharmacokinetics The pharmacokinetics of etodolac have been evaluated in 267 normal subjects, 44 elderly patients (>65 years old), 19 patients with renal failure (creatinine clearance 37 to 88 mL/min), 9 patients on hemodialysis, and 10 patients with compensated hepatic cirrhosis. Etodolac, when administered orally, exhibits kinetics that are well described by a two-compartment model with first-order absorption. Lodine has no apparent pharmacokinetic interaction when administered with phenytoin, glyburide, furosemide or hydrochlorothiazide. ABSORPTIONAbsorption The systemic bioavailability of etodolac from Lodine is 100% as compared to solution and at least 80% as determined from mass balance studies. Etodolac is well absorbed and had a relative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation, is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (± 1 SD) peak plasma concentrations (Cmax) range from approximately 14 ± 4 to 37 ± 9 µg/mL after 200 to 600 mg single doses and are reached in 80 ± 30 minutes (see Table 1 for summary of pharmacokinetic parameters). The dose-proportionality based on AUC (the area under the plasma concentration-time curve) (AUC) is linear following doses up to 600 mg every 12 hours. Peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg every 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis of lower doses. The extent of absorption of etodolac is not affected when Lodine is administered after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration by 1.4 to 3.8 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 5 Table 1. Etodolac Steady-State Pharmacokinetic Parameters (N=267) Kinetic Parameters Mean ± SD Extent of oral absorption (bioavailability) [F] ≥ 80% Oral-dose clearance [CL/F] 47 ± 16 mL/h/kg Steady-state volume [Vss/F] 362 ± 129 mL/kg Distribution half-life [t1/2, α] 0.71 ± 0.50 h Terminal half-life [t1/2, β] 7.3 ± 4.0 h Antacid Effects The extent of absorption of etodolac is not affected when Lodine is administered with an antacid. Coadministration with an antacid decreases the peak concentration reached by about 15 to 20%, with no measurable effect on time-to-peak. Food Effects The extent of absorption of etodolac is not affected when Lodine is administered after a meal. Food intake, however, reduces the peak concentration reached by approximately one half and increases the time-to-peak concentration by 1.4 to 3.8 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 6 Table 1. Mean (CV%)† Pharmacokinetic Parameters of Lodine in Normal Healthy Adults and Various Special Populations[1] PK Parameters Normal Healthy Adults (18-65)∗ (n=179) Healthy Males (18-65) (n=176) Healthy Females (27-65) (n=3) Elderly (>65) (70-84) Hemodialysis (24-65) (n=9) Dialysis Dialysis On Off Renal Impairment (46-73) (n=10) Hepatic Impairment (34-60) (n=9) Tmaxh 1.4 (61%)† 1.4 (60%) 1.7 (60%) 1.2 (43%) 1.7 (88%) 0.9 (67%) 2.1 (46%) 1.1 (15%) Oral Clearance, mL/h/kg (CL/F) 49.1 (33%) 49.4 (33%) 35.7 (28%) 45.7 (27%) NA NA 58.3 (19%) 42.0 (43%) Apparent Volume of Distribution, mL/kg (Vd/F) 393 (29%) 394 (29%) 300 (8%) 414 (38%) NA NA NA NA Terminal Half-Life, h 6.4 (22%) 6.4 (22%) 7.9 (35%) 6.5 (24%) 5.1 (22%) 7.5 (34%) NA 5.7 (24%) †% Coefficient of variation Age Range (years) NA = not available DistributionDistribution Etodolac has an apparent steady-state volume of distribution about 0.362 L/kg. Within the therapeutic dose range, etodolac is more than 99% bound to plasma proteins. The free fraction is less than 1% and is independent of etodolac total concentration over the dose range studied. The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin. The free fraction is less than 1% and is independent of etodolac total concentration over the dose range studied. It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Data from in vitro studies, using peak serum concentrations at reported therapeutic doses in humans, show that the etodolac free fraction is not significantly altered by acetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid. MetabolismMetabolism Etodolac is extensively metabolized in the liver., with renal elimination of etodolac and its metabolites being the primary route of excretion. The intersubject variability of etodolac plasma levels, achieved after recommended doses, is substantial.The role, if any, of a specific cytochrome P450 system in the metabolism of etodolac is unknown. Several etodolac metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8- hydroxylated-etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated- etodolac metabolite does not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 7 Protein Binding Data from in vitro studies, using peak serum concentrations at reported therapeutic doses in humans, show that the etodolac free fraction is not significantly altered by acetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid. EliminationExcretion The mean plasmaoral clearance of etodolac, following oral dosing is 4749 (± 16) mL/h/kg., and terminal disposition half-life is 7.3 (± 4.0) hours. Approximately 72% of the administered dose is recovered in the urine as the following, indicated as % of the administered doseApproximately 1% of a Lodine dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite:  etodolac, unchanged 1%  etodolac glucuronide 13%  hydroxylated metabolites (6-, 7-, and 8-OH) 5%  hydroxylated metabolite glucuronides 20%  unidentified metabolites 33% Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild to moderate renal dysfunction is generally necessary. The terminal half-life (t1/2) of etodolac is 6.4 hours (22% CV). In patients with severe renal dysfunction or undergoing hemodialysis, dosing adjustment is not generally necessary. Fecal excretion accounted for 16% of the dose. SPECIAL POPULATIONSSpecial Populations Elderly PatientsGeriatric In Lodine clinical studies, no overall differences in safety or effectiveness were observed between these patients and younger patients. In pharmacokinetic studies,etodolac clearance was reduced by about 15% in older patients (>65 years of age). In these studies, age was shown not to have any effect on etodolac half-life or protein binding, and there was no change in expected drug accumulation. Therefore, Nno dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics (see PRECAUTIONS, Geriatric Use). The elderly may need dosage adjustment, however, on the basis of body size (see Precautions—GERIATRIC POPULATION), as they may be more sensitive to antiprostaglandin effects than younger patients (see Precautions—GERIATRIC POPULATION). Etodolac is eliminated primarily by the kidney. 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 PRECAUTIONS, General, Renal Effects). (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) NDA 18-922/S-021 Page 8 Renal Impairment Studies in patients with mild-to-moderate renal impairment (creatinine clearance 37 to 88 mL/min) showed no significant differences in the disposition of total and free etodolac. In patients undergoing hemodialysis, there was a 50% greater apparent clearance of total etodolac, due to a 50% greater unbound fraction. Free etodolac clearance was not altered, indicating the importance of protein binding in etodolac’s disposition. Nevertheless, etodolac is not dialyzable. Pediatric Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Race Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion. Hepatic ImpairmentInsufficiency Etodolac is predominantly metabolized by the liver. In patients with compensated hepatic cirrhosis, the disposition of total and free etodolac is not altered. Patients with acute and chronic hepatic diseases do not generally require reduced doses of etodolac compared to patients with normal hepatic function. However, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure. Etodolac plasma protein binding did not change in patients with compensated hepatic cirrhosis given Lodine.Although no dosage adjustment is generally required in this patient population, etodolac clearance is dependent on hepatic function and could be reduced in patients with severe hepatic failure. Renal Insufficiency Lodine pharmacokinetics have been investigated in subjects with renal insufficiency. Etodolac renal clearance was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance 37 to 88 mL/min). Furthermore, there were no significant differences in the disposition of total and free etodolac in these patients. However, etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. In patients undergoing hemodialysis, there was a 50% greater apparent clearance of total etodolac, due to a 50% greater unbound fraction. Free etodolac clearance was not altered, indicating the importance of protein binding in etodolac’s disposition. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis. Clinical TrialsCLINICAL STUDIES ANALGESIAAnalgesia Controlled clinical trials in analgesia were single-dose, randomized, double-blind, parallel studies in three pain models, including dental extractions. The analgesic effective dose for Lodine established in these acute pain models was 200 to 400 mg. The onset of analgesia occurred approximately 30 minutes after oral administration. Lodine 200 mg provided efficacy comparable to that obtained with aspirin (650 mg). Lodine 400 mg provided efficacy comparable to that obtained with acetaminophen with codeine (600 mg + 60 mg). The peak analgesic effect was between 1 to 2 hours. Duration of relief averaged 4 to 5 hours for 200 mg of Lodine and 5 to 6 hours for 400 mg of Lodine as measured by when approximately half of the patients required remedication. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 9 OSTEOARTHRITISOsteoarthritis The use of Lodine in managing the signs and symptoms of osteoarthritis of the hip or knee was assessed in double-blind, randomized, controlled clinical trials in 341 patients. In patients with osteoarthritis of the knee, Lodine, in doses of 600 to 1000 mg/day, was better than placebo in two studies. The clinical trials in osteoarthritis used b.i.d. dosage regimens. RHEUMATOID ARTHRITISRheumatoid Arthritis In a 3-month study with 426 patients, Lodine 300 mg b.i.d. was effective in management of rheumatoid arthritis and comparable in efficacy to piroxicam 20 mg/day. In a long-term study with 1,446 patients in which 60% of patients completed 6 months of therapy and 20% completed 3 years of therapy, Lodine in a dose of 500 mg b.i.d. provided efficacy comparable to that obtained with ibuprofen 600 mg q.i.d. In clinical trials of rheumatoid arthritis patients, Lodine has been used in combination with gold, d-penicillamine, chloroquine, corticosteroids, and methotrexate. Indications and UsageINDICATIONS AND USAGE Lodine (etodolac capsules and tablets) is indicated: for • For acute and long-term use in the management of signs and symptoms of the following: 1. oOsteoarthritis and 2. rRheumatoid arthritis. • Lodine is also indicated fFor the management of acute pain. ContraindicationsCONTRAINDICATIONS Lodine is contraindicated in patients with known hypersensitivity to etodolac. Lodine should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs Lodine have been reported in such patients (see Warnings WARNINGS, —Anaphylactoid Reactions Anaphylactoid Reactions and PRECAUTIONS, General, Pre-existing Asthma). WarningsWARNINGS RISK OF GASTROINTESTINAL (GI) ULCERATION, BLEEDING, AND PERFORATION WITH NONSTEROIDAL, ANTI-INFLAMMATORY DRUG (NSAID) THERAPY Gastrointestinal (GI) Effects—Risk of GI Ulceration, Bleeding, and Perforation Serious GI toxicity, such as inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated chronically with NSAIDs. Although minor upper GI problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs, even in the absence of previous GI-tract symptoms. In patients observed in clinical trials of such agents for several months’ to 2 years’ duration, symptomatic upper GI ulcers, gross bleeding, or perforation appears to occur in approximately 1% of patients treated for 3 to 6 months and in about 2% to 4% of patients treated for 1 year. Physicians should This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 10 inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Studies have shown that patients with a prior history of peptic ulcer disease, and/or gastrointestinal bleeding, and who use NSAIDs have a greater than 10-fold risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status. Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity. ANAPHYLACTOID REACTIONSAnaphylactoid Reactions As with other NSAIDS, Aanaphylactoid reactions may occur in patients without prior exposure to etodolacLodine. Lodine should not be given to patients with the aspirin triad. The triad This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDsnonsteroidal anti-inflammatory drugs. Fatal reactions have been reported in such patients (see Contraindications CONTRAINDICATIONS and PrecautionsPRECAUTIONS,— General, Pre-existing Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. ADVANCED RENAL DISEASEAdvanced Renal Disease In cases with advanced kidney disease, treatment with Lodine is not recommended. However, if NSAID therapy must be initiated, close monitoring of the patient’s kidney function is advisable as with other NSAIDs, treatment with Lodine should only be initiated with close monitoring of the patient’s kidney function (see Precautions—PRECAUTIONS, General, Renal Effects). PREGNANCYPregnancy In late pregnancy, the third trimester, as with other NSAIDs, Lodine should be avoided because it may cause premature closure of the ductus arteriosus (see Precautions—PRECAUTIONS, Pregnancy, Teratogenic Effects—Pregnancy Category C). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 11 PrecautionsPRECAUTIONS GENERAL PRECAUTIONSGeneral Lodine cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered solely if a decision is made to discontinue corticosteroids. The pharmacological activity of Lodine in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Lodine. These laboratory abnormalities may disappear, remain essentially unchanged, or progress with continued therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Lodine. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Lodine should be discontinued. Renal Effects Caution should be used when initiating treatment with Lodine in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Lodine. As with other NSAIDs, long-term administration of etodolac to rats has resulted in renal papillary necrosis and other renal medullary changes. Renal pelvic transitional epithelial hyperplasia, a spontaneous change occurring with variable frequency, was observed with increased frequency in treated male rats in a 2-year chronic study. A second form of renal toxicity encountered with Lodine, as with other NSAIDs, is seen in patients with conditions in which renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose- dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, or liver dysfunction;, those taking diuretics; and ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state. Etodolac metabolites are eliminated primarily by the kidneys. The extent to which the inactive glucuronide metabolites may accumulate in patients with renal failure has not been studied. As with other drugs whose metabolites are excreted by the kidney, the possibility that adverse reactions (not listed in Adverse ReactionsADVERSE REACTIONS) may be attributable to these metabolites should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 12 Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Lodine. These abnormalities may disappear, remain essentially unchanged, or progress with continued therapy. Meaningful elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with Lodine. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Lodine. Rare cases of liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), Lodine should be discontinued. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs including Lodine. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Lodine, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. All drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent with platelet function and vascular responses to bleeding. NSAIDS inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Lodine who may be adversely affected by alteration in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Fluid Retention and Edema Fluid retention and edema have been observed in some patients taking NSAIDS, including Lodine. Therefore, as with other NSAIDs, Lodine should be used with caution in patients with fluid retention, hypertension, or heart failure. Pre-existing Asthma About 10% of pPatients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthmas has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, etodolacLodine should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with pre- existing asthma. INFORMATION FOR PATIENTSInformation For Patients Lodine, like other drugs of its class, can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptom. Patients should be informed of the importance of this follow-up (see WARNINGS, Gastrointestinal (GI) EffectsRisk of GI Ulceration, Bleeding, and Perforation). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 13 Physicians may wish to discuss with their patients the potential risks (see WarningsPrecautions, Adverse Reactions) and likely benefits of non-steroidal anti-inflammatory drug treatment. Patients on Lodine (etodolac capsules and tablets) should report to their physicians signs or symptoms of gastrointestinal ulceration or bleeding, blurred vision or other eye symptoms, skin rash, weight gain, or edema. Because serious gastrointestinal tract ulcerations and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulcerations and bleeding and should inform them of the importance of this follow-up (see Warnings—,RISK OF GI ULCERATION, BLEEDING AND PERFORATION WITH NONSTEROIDAL ANTI- INFLAMMATORY THERAPY). Patients should also be instructed to seek medical emergency help in case of an occurrence of anaphylactoid reactions (see Warnings WARNINGS). LABORATORY TESTSLaboratory Tests Patients on long-term treatment with Lodine, as with other NSAIDs, should have their CBC and a chemistry profile hemoglobin or hematocrit checked periodically for signs or symptoms of anemia. Appropriate measures should be taken in case such signs of anemia occur. If clinical signs and symptoms consistent with liver or renal disease develop or if systemic manifestations occur (e.g., eosinophilia, rash, etc.) and if abnormal liver tests are detected, persist or worsen, Lodine should be discontinued. DRUG INTERACTIONSDrug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE- inhibitors (see PRECAUTIONS, General, Renal Effects). Antacids The concomitant administration of antacids has no apparent effect on the extent of absorption of Lodine. However, antacids can decrease the peak concentration reached by 15% to 20% but have no detectable effect on the time-to-peak. Aspirin When Lodine is administered with aspirin, its protein binding is reduced, although the clearance of free etodolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of Lodine and aspirin is not generally recommended because of the potential of increased adverse effects. Cyclosporine, Digoxin, Lithium, Methotrexate Lodine, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs leading to elevated serum levels of cyclosporine, digoxin, lithium, and methotrexate, and increased toxicity. Nephrotoxicity associated with cyclosporine may also be enhanced. Patients receiving these drugs who are given Lodine, or any other NSAID, and particularly those patients with altered renal function, should be observed for the development of the specific toxicities of these drugs. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 14 Diuretics Etodolac has no apparent pharmacokinetic interaction when administered with furosemide or hydrochlorothiazide. Nevertheless, clinical studies, as well as postmarketing observations have shown that Lodine can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see PRECAUTIONS, General, Renal Effects), as well as to assure diuretic efficacy. Glyburide Etodolac has no apparent pharmacokinetic interaction when administered with glyburide. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Phenylbutazone Phenylbutazone causes increase (by about 80%) in the free fraction of etodolac. Although in vivo studies have not been done to see if etodolac clearance is changed by coadministration of phenylbutazone, it is not recommended that they be coadministered. Phenytoin Etodolac has no apparent pharmacokinetic interaction when administered with phenytoin. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that of users of either drug alone. Short-term pharmacokinetic studies have demonstrated that concomitant administration of warfarin and Lodine (etodolac capsules and tablets) results in reduced protein binding of warfarin, but there was no change in the clearance of free warfarin. There was no significant difference in the pharmacodynamic effect of warfarin administered alone and warfarin administered with Lodine as measured by prothrombin time. Thus, concomitant therapy with warfarin and Lodine should not require dosage adjustment of either drug. However, caution should be exercised because there have been a few spontaneous reports of prolonged prothrombin times, with or without bleeding, in Lodineetodolac-treated patients receiving concomitant warfarin therapy. Caution should be exercised because interactions have been seen with other NSAIDs. DRUG/LABORATORY TEST INTERACTIONSDrug/Laboratory Test Interactions The urine of patients who take Lodine can give a false-positive reaction for urinary bilirubin (urobilin) due to the presence of phenolic metabolites of etodolac. Diagnostic dip-stick methodology, used to detect ketone bodies in urine, has resulted in false-positive findings in some patients treated with Lodine. Generally, this phenomenon has not been associated with other clinically significant events. No dose relationship has been observed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 15 Lodine treatment is associated with a small decrease in serum uric acid levels. In clinical trials, mean decreases of 1 to 2 mg/dL were observed in arthritic patients receiving etodolac (600 mg to 1000 mg/day) after 4 weeks of therapy. These levels then remained stable for up to 1 year of therapy. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY Carcinogenesis, Mutagenesis, and Impairment of Fertility No carcinogenic effect of etodolac was observed in mice or rats receiving oral doses of 15 mg/kg/day (45 to 89 mg/m2, respectively) or less for periods of 2 years or 18 months, respectively. Etodolac was not mutagenic in in vitro tests performed with S. typhimurium and mouse lymphoma cells as well as in an in vivo mouse micronucleus test. However, data from the in vitro human peripheral lymphocyte test showed an increase in the number of gaps (3.0 to 5.3% unstained regions in the chromatid without dislocation) among the Lodine-treated cultures (50 to 200 µg/mL) compared to negative controls (2.0%); no other difference was noted between the controls and drug-treated groups. Etodolac showed no impairment of fertility in male and female rats up to oral doses of 16 mg/kg (94 mg/m2). However, reduced implantation of fertilized eggs occurred in the 8 mg/kg group. PREGNANCYPregnancy Teratogenic Effects—Pregnancy Category C In teratology studies, isolated occurrences of alterations in limb development were found and included polydactyly, oligodactyly, syndactyly, and unossified phalanges in rats and oligodactyly and synostosis of metatarsals in rabbits. These were observed at dose levels (2 to 14 mg/kg/day) close to human clinical doses. However, the frequency and the dosage group distribution of these findings in initial or repeated studies did not establish a clear drug or dose-response relationship. Animal reproduction studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Lodine should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Because of the known effects of NSAIDs on parturition and on the human fetal cardiovascular system with respect to closure of the ductus arteriosus, use during late pregnancy, the third trimester, should be avoided. LABOR AND DELIVERYLabor and Delivery In rat studies with etodolacNSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Lodine on labor and delivery in pregnant women are unknown. NURSING MOTHERSNursing Mothers It is not known whether etodolac 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 etodolacLodine, 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 USEPediatric Use Safety and effectiveness in pediatric patients below the age of 18 years have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 16 GERIATRIC POPULATIONGeriatric Use As with any NSAID, however, caution should be exercised in treating the elderly, and when individualizing their dosage, extra care should be taken when increasing the dose because the elderly seem to tolerate NSAID side effects less well than younger patients. In patients 65 years and older, no substantial differences in the side effect profile of Lodine were seen compared with the general population (see Clinical Pharmacology—PHARMACOKINETICS).In Lodine clinical studies, no overall differences in safety or effectiveness were observed between these patients and younger patients. In pharmacokinetic studies, age was shown not to have any effect on etodolac half-life or protein binding, and there was no change in expected drug accumulation. Therefore, no dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics (see CLINICAL PHARMACOLOGY, Special Populations). Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients (see WARNINGS and PRECAUTIONS, General, Renal Effects). In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Therefore, caution should be exercised in treating the elderly and when increasing the dose (see WARNINGS). Etodolac is eliminated primarily by the kidney. 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 PRECAUTIONS, General, Renal Effects). Adverse ReactionsADVERSE REACTIONS In patients taking Lodine or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1-10% of patients are: Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting. Other events including: abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritis, rashes, tinnitus. Adverse-reaction information for Lodine was derived from 2,629 arthritic patients treated with Lodine (etodolac capsules and tablets) in double-blind and open-label clinical trials of 4 to 320 weeks in duration and worldwide postmarketing surveillance studies. In clinical trials, most adverse reactions were mild and transient. The discontinuation rate in controlled clinical trials, because of adverse events, was up to 10% for patients treated with Lodine. New patient complaints (with an incidence greater than or equal to 1%) are listed below by body system. The incidences were determined from clinical trials involving 465 patients with osteoarthritis treated with 300 to 500 mg of Lodine b.i.d. (i.e., 600 to 1000 mg/day). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 17 INCIDENCE GREATER THAN OR EQUAL TO 1%—PROBABLY CAUSALLY RELATEDIncidence Greater Than Or Equal To 1%—Probably Causally Related Body as a whole—Chills and fever. Digestive system—Dyspepsia (10%), abdominal pain, diarrhea, flatulence, nausea, constipation, gastritis, melena, vomiting. Nervous system—Asthenia/malaise, dizziness, depression, nervousness. Skin and appendages—Pruritus, rash. Special senses—Blurred vision, tinnitus. Urogenital system—Dysuria, urinary frequency. Drug-related patient complaints occurring in 3 to 9% of patients treated with Lodine. Drug-related patient-complaints occurring in fewer than 3%, but more than 1%, are unmarked. INCIDENCE LESS THAN 1%—PROBABLY CAUSALLY RELATEDIncidence Less Than 1%—Probably Causally Related (Adverse reactions reported only in worldwide postmarketing experience, not seen in clinical trials, are considered rarer and are italicized.) Body as a whole—Allergic reaction, anaphylactic/anaphylactoid reactions (including shock). Cardiovascular system—Hypertension, congestive heart failure, flushing, palpitations, syncope, vasculitis (including necrotizing and allergic). Digestive system—Thirst, dry mouth, ulcerative stomatitis, anorexia, eructation, elevated liver enzymes, cholestatic hepatitis, hepatitis, cholestatic jaundice, duodenitis, jaundice, hepatic failure, liver necrosis, peptic ulcer with or without bleeding and/or perforation, intestinal ulceration, pancreatitis. Hemic and lymphatic system—Ecchymosis, anemia, thrombocytopenia, bleeding time increased, agranulocytosis, hemolytic anemia, leukopenia, neutropenia, pancytopenia. Metabolic and nutritional—Edema, serum creatinine increase, hyperglycemia in previously controlled diabetic patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 18 Nervous system—Insomnia, somnolence. Respiratory system—Asthma, pulmonary infiltration with eosinophilia. Skin and appendages—Angioedema, sweating, urticaria, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson Syndrome, toxic epidermal necrolysis, hyperpigmentation, erythema multiforme. Special senses—Photophobia, transient visual disturbances. Urogenital system—Elevated BUN, renal failure, renal insufficiency, renal papillary necrosis. INCIDENCE LESS THAN 1%—CAUSAL RELATIONSHIP UNKNOWNIncidence Less Than 1%—Causal Relationship Unknown (Medical events occurring under circumstances where causal relationship to Lodine is uncertain. These reactions are listed as alerting information for physicians.) Body as a whole—Infection, headache. Cardiovascular system—Arrhythmias, myocardial infarction, cerebrovascular accident. Digestive system—Esophagitis with or without stricture or cardiospasm, colitis. Metabolic and nutritional—Change in weight. Nervous system—Paresthesia, confusion. Respiratory system—Bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis. Skin and appendages—Alopecia, maculopapular rash, photosensitivity, skin peeling. Special senses—Conjunctivitis, deafness, taste perversion. Urogenital system—Cystitis, hematuria, leucorrhea, renal calculus, interstitial nephritis, uterine bleeding irregularities. Additional Adverse Reactions Reported with NSAIDS Body as a wholeSepsis, death Cardiovascular systemTachycardia Digestive systemGastric ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis Hemic and lymphatic systemLymphadenopathy Nervous systemAnxiety, dream abnormalities, convulsions, coma, hallucinations, meningitis, tremors, vertigo Respiratory systemRespiratory depression, pneumonia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 19 Urogenital systemOliguria/polyuria, proteinuria OverdosageOVERDOSAGE Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur and coma has occurred following massive ibuprofen or mefenamic-acid overdose. Hypertension, acute renal failure, and respiratory depression may occur but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following overdose. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 mg in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose).Gut decontamination may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with an osmotic cathartic. Forced diuresis, alkalinization of the urine, hemodialysis, or hemoperfusion would probably not be useful due to etodolac’s high protein binding. Dosage and AdministrationDOSAGE AND ADMINISTRATION As with other NSAIDs, the lowest dose and longest dosing interval should be sought for each patient. Therefore, after observing the response to initial therapy with Lodine, the dose and frequency should be adjusted to suit an individual patient’s needs. Dosage adjustment of Lodine is generally not required in patients with mild to moderate renal impairment. Etodolac should be used with caution in such patients, because, as with other NSAIDs, it may further decrease renal function in some patients with impaired renal function. (see Precautions— GENERAL PRECAUTIONS, Renal Effects PRECAUTIONS, General, Renal Effects). ANALGESIAAnalgesia The recommended total daily dose of Lodine for acute pain is up to 1000 mg, given as 200-400 mg every 6 to 8 hours. In some patients, if the potential benefits outweigh the risks; the dose may be increased to 1200 mg/day in order to achieve a therapeutic benefit that might not have been achieved with 1000 mg/day. Doses of etodolac greater than 1000 mg/day have not been adequately evaluated in well-controlled clinical trials. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 20 OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS Osteoarthritis and Rheumatoid Arthritis The recommended starting dose of Lodine for the management of the signs and symptoms of osteoarthritis or rheumatoid arthritis is: 300 mg b.i.d., t.i.d., or 400 mg b.i.d., or 500 mg b.i.d. During long-term administration, the dose of Lodine may be adjusted up or down depending on the clinical response of the patient.” A lower dose of 600 mg/day may suffice for long-term administration. In patients who tolerate 1000 mg/day, the dose may be increased to 1200 mg/day when a higher level of therapeutic activity is required. When treating patients with higher doses, the physician should observe sufficient increased clinical benefit to justify the higher dose. Physicians should be aware that doses above 1000 mg/day have not been adequately evaluated in well-controlled clinical trials. In chronic conditions, a therapeutic response to therapy with Lodine is sometimes seen within one week of therapy, but most often is observed by two weeks. After a satisfactory response has been achieved, the patient’s dose should be reviewed and adjusted as required. HOW SUPPLIED Lodine (etodolac capsules and tablets) is available as: Lodine (etodolac capsules) Capsules 200 mg capsules (light gray with one wide red band with LODINE 200/white with two narrow red bands) in bottles of 100, NDC 0046-0738-81 300 mg capsules (light gray with one wide red band with LODINE 300/light gray with two narrow red bands) in bottles of 100, NDC 0046-0739-81 Store at controlled room temperature 20°-25°C (68°-77°F), protected from moisture. Lodine (etodolac tablets) Tablets 400 mg tablets (yellow-orange, oval, film-coated tablet, debossed LODINE 400 on one side) in bottles of 100, NDC 0046-0761-81 Store at controlled room temperature 20°-25°C (68°-77°F). Store tablets in original container until ready to use. Dispense in light-resistant container. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-922/S-021 Page 21 500 mg tablets (blue, oval, film-coated tablet, branded LODINE 500 on one side) in bottles of 100, NDC 0046-0787-81 Store at controlled room temperature 20°-25°C (68°-77°F). Store tablets in original container until ready to use. Dispense in a light-resistant container. The appearance of these capsules is a registered trademark of Wyeth Pharmaceuticals and the appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Wyeth Pharmaceuticals Inc. W10484C001 Philadelphia, PA 19101 ET02 Rev 11/03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:02.321699	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018922s021lbl.pdf', 'application_number': 18922, 'submission_type': 'SUPPL ', 'submission_number': 21}
11,366	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	2025-02-12T13:45:02.537322	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016608s100s102,018281s049s050,018927s041s042,020234s031s033lbl.pdf', 'application_number': 18927, 'submission_type': 'SUPPL ', 'submission_number': 41}
11,367	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	2025-02-12T13:45:02.788409	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016608s100s102,018281s049s050,018927s041s042,020234s031s033lbl.pdf', 'application_number': 18927, 'submission_type': 'SUPPL ', 'submission_number': 42}
11,368	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	2025-02-12T13:45:02.999115	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016608s103,018281s051,018927s044,020234s035lbl.pdf', 'application_number': 18927, 'submission_type': 'SUPPL ', 'submission_number': 44}
11,369	NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 1 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 Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 2 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. 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: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 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 0.5-25 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 Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 4 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. 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. Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 5 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 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. Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 6 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 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. Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 7 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 Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 8 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. 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). Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 9 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®). 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. Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 10 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 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: Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 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, 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 co medications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be expected to cause, decreased levels of the following: 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. Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 12 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. 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. Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 13 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, 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. 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. Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 14 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: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 15 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. Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 16 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 6-12 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). Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 016608/S-107 NDA 018281/S-055 NDA 018927/S-048 NDA 020234/S-040 FDA Approved Labeling Text dated 12/11/2012 Page 17 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). 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: 3219002 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: 3219002 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. Reference ID: 3219002 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  trouble sleeping (insomnia)  new or worse irritability  acting aggressive, being angry, or violent Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  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  have or ever had kidney problems Reference ID: 3219002 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 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 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? Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  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. 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. Reference ID: 3219002 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 Chewable Tablets above 30°C (86°F).  Keep TEGRETOL Chewable Tablets out of the light.  Keep TEGRETOL Chewable Tablets 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 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 T2012-167/T2011-32 November 2012/March 2011 Reference ID: 3219002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:03.007589	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016608s107,018281s055,018927s048,020234s040lbl.pdf', 'application_number': 18927, 'submission_type': 'SUPPL ', 'submission_number': 48}
11,371	NDA 18-936/S-064 Approved Labeling Enclosure Page 1 1 ENCLOSURE [Note: Below is the Agency’s final labeling for Prozac to incorporate the new pediatric major depressive disorder and obsessive compulsive disorder changes to the Prozac labeling.] PROZAC® FLUOXETINE HYDROCHLORIDE DESCRIPTION Prozac® (fluoxetine hydrochloride) is a psychotropic drug for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (SarafemTM, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p- tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol), 20 mg (64.7 µmol), or 40 mg (129.3 µmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10 mg and 20 mg Pulvules also contain F D & C Blue No. 1, and the 40 mg Pulvule also contains F D & C Blue No. 1 and F D & C Yellow No. 6. Each tablet contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol) of fluoxetine. The tablets also contain microcrystalline cellulose, magnesium stearate, crospovidone, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and yellow iron oxide. In addition to the above ingredients, the 10 mg tablet contains F D & C Blue No. 1 aluminum lake, and polysorbate 80. The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 µmol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. Prozac Weekly capsules, a delayed release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 µmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 2 2 CLINICAL PHARMACOLOGY Pharmacodynamics: The antidepressant, antiobsessive-compulsive, and antibulimic actions of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. Absorption, Distribution, Metabolism, and Excretion: Systemic Bioavailability--In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The Pulvule, tablet, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayed release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate release formulations. Protein Binding--Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1- glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS). Enantiomers--Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism--Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R- norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical Issues Related to Metabolism/Elimination--The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine's clinical use. Variability in Metabolism--A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450IID6. Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S- fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 3 3 metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the four active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non- IID6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine's metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors, involves the P450IID6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see Drug Interactions under PRECAUTIONS). Accumulation and Slow Elimination--The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of Prozac. Weekly Dosing—Administration of Prozac Weekly once-weekly results in increased fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared to once daily dosing (for fluoxetine: 24% [daily] to 164% [weekly] and for norfluoxetine: 17% [daily] to 43% [weekly]). Plasma concentrations may not necessarily be predictive of clinical response. Peak concentrations from once-weekly doses of Prozac Weekly capsules of fluoxetine are in the range of the average concentration for 20 mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20 mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly dosing are in relative proportion to the total dose administered. Average steady state fluoxetine concentrations are approximately 50% lower following the once-weekly regimen compared to the once-daily regimen. Cmax for fluoxetine following the 90 mg dose was approximately 1.7 fold higher than the Cmax value for the established 20 mg once daily regimen following transition the next day to the once- weekly regimen. In contrast, when the first 90 mg once weekly dose and the last 20 mg once daily dose were separated by one week, Cmax values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 4 4 Liver Disease--As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared to the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared to the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Renal Disease--In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable to those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (see Use in Patients with Concomitant Illness under PRECAUTIONS and DOSAGE AND ADMINISTRATION). Age— Geriatric Pharmacokinetics--The disposition of single doses of fluoxetine in healthy elderly subjects (greater than 65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥ 60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse events was observed in those elderly patients. Pediatric Pharmacokinetics (Children and Adolescents)--Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with major depressive disorder or obsessive compulsive disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 ng/mL and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5- fold higher than in adolescents (195 ng/mL and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with major depressive disorder. Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. Clinical Trials: Major Depressive Disorder— Daily Dosing: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 5 5 Adult--The efficacy of Prozac for the treatment of patients with major depressive disorder (≥ 18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Prozac was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. Two 6-week controlled studies (N=671, randomized) comparing Prozac 20 mg, and placebo have shown Prozac 20 mg daily, to be effective in the treatment of elderly patients (≥ 60 years of age) with major depressive disorder. In these studies, Prozac produced a significantly higher rate of response and remission as defined respectively by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of < 8. Prozac was well tolerated and the rate of treatment discontinuations due to adverse events did not differ between Prozac (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of < 7 during each of the last 3 weeks of open-label treatment and absence of major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week open treatment phase on Prozac 20 mg/day. These patients (N=298) were randomized to continuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of major depressive disorder for 2 weeks or a modified HAMD-17 score of > 14 for 3 weeks) was observed for patients taking Prozac compared to those on placebo. Pediatric (Children and Adolescents)--The efficacy of Prozac 20 mg/day for the treatment of major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) has been studied in two 8- to 9-week placebo- controlled clinical trials. In both studies independently, Prozac produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Weekly dosing for maintenance/continuation treatment: A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded (defined as having a modified HAMD-17 score of < 9, a CGI-Severity rating of < 2, and no longer meeting criteria for major depressive disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with Prozac 20 mg once-daily. These patients were randomized to double-blind, once-weekly continuation treatment with Prozac Weekly, Prozac 20 mg once-daily, or placebo. Prozac Weekly once-weekly and Prozac 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of depressive symptoms) compared to placebo for a period of 25 weeks. However, the equivalence of these two treatments during continuation therapy has not been established. Obsessive Compulsive Disorder— Adult--The effectiveness of Prozac for the treatment for obsessive compulsive disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once a day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 6 6 mean reductions of approximately 4 to 6 units on the YBOCS total score, compared to a 1-unit reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared to a 1-unit reduction for placebo patients. While there was no indication of a dose response relationship for effectiveness in Study 1, a dose response relationship was observed in Study 2, with numerically better responses in the two higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Prozac Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No Change 64% 41% 33% 29% Minimally Improved 17% 23% 28% 24% Much Improved 8% 28% 27% 28% Very Much Improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (Children and Adolescents)--In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD, patients received Prozac 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Prozac produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. Bulimia Nervosa--The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of Prozac or placebo in the morning. Patients in the 16-week study received a fixed Prozac dose of 60 mg/day (once a day) or placebo. Patients in these three studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these three studies, Prozac 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg vs placebo was present as early as Week 1 and persisted throughout each study. The Prozac related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between Prozac 60 mg, and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 7 7 baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. In a longer-term trial, 150 patients meeting (DSM-IV) criteria for bulimia nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with Prozac 60 mg/day, were randomized to continuation of Prozac 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgement that the patient had relapsed. Patients receiving continued Prozac 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. Panic Disorder—The effectiveness of Prozac in the treatment of panic disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia. Study 1 (N = 180 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% vs. 28%, respectively. Study 2 (N = 214 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percent of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% vs. 44%, respectively. INDICATIONS AND USAGE Major Depressive Disorder--Prozac is indicated for the treatment of major depressive disorder. Adult--The efficacy of Prozac was established in 5- and 6-week trials with depressed adult and geriatric outpatients (≥ 18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood; loss of interest in usual activities; significant change in weight and/or appetite; insomnia or hypersomnia; psychomotor agitation or retardation; increased fatigue; feelings of guilt or worthlessness; slowed thinking or impaired concentration; a suicide attempt or suicidal ideation. The effects of Prozac in hospitalized depressed patients have not been adequately studied. The efficacy of Prozac 20 mg once-daily in maintaining a response in major depressive disorder for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) was demonstrated in a placebo-controlled trial. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 8 8 The efficacy of Prozac Weekly once-weekly in maintaining a response in major depressive disorder has been demonstrated in a placebo-controlled trial for up to 25 weeks following open-label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38 weeks. However, it is unknown whether or not Prozac Weekly given on a once-weekly basis provides the same level of protection from relapse as that provided by Prozac 20 mg daily (see Clinical Trials under CLINICAL PHARMACOLOGY). Pediatric (Children and Adolescents)--The efficacy of Prozac in children and adolescents was established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY). The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should be reevaluated periodically. Obsessive-Compulsive Disorder— Adult--Prozac is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of Prozac was established in 13-week trials with obsessive-compulsive outpatients whose diagnoses corresponded most closely to the DSM-III-R category of obsessive-compulsive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY). Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. The effectiveness of Prozac in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Pediatric (Children and Adolescents)--The efficacy of Prozac in children and adolescents was established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in DSM- IV (see Clinical Trials under CLINICAL PHARMACOLOGY). Bulimia Nervosa--Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa. The efficacy of Prozac was established in 8 to 16 week trials for adult outpatients with moderate to severe bulimia nervosa, i.e., at least three bulimic episodes per week for 6 months (see Clinical Trials under CLINICAL PHARMACOLOGY). The efficacy of Prozac 60 mg/day in maintaining a response, in patients with bulimia who responded during an 8-week acute treatment phase while taking Prozac 60 mg/day and were then observed for relapse during a period of up to 52 weeks, was demonstrated in a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 9 9 placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Panic Disorder—Prozac is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks, and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of Prozac was established in two 12-week clinical trials in patients whose diagnoses corresponded to the DSM-IV category of panic disorder (see Clinical Trials under CLINICAL PHARMACOLOGY). Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 or more of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear of dying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes. The effectiveness of Prozac in long-term use, that is, for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Prozac is contraindicated in patients known to be hypersensitive to it. Monoamine Oxidase Inhibitors--There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Prozac should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses [see Accumulation and Slow Elimination under CLINICAL PHARMACOLOGY]) should be allowed after stopping Prozac before starting an MAOI. Thioridazine—Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after Prozac has been discontinued (see WARNINGS). WARNINGS Rash and Possibly Allergic Events--In US fluoxetine clinical trials as of May 8, 1995, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 10 10 carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely. In premarketing clinical trials, two patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of Prozac, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac should be discontinued. Potential Interaction with Thioridazine—In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared to the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of cytochrome P450IID6 isozyme activity. Thus, this study suggests that drugs which inhibit P450IID6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS). Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS). PRECAUTIONS General Anxiety and Insomnia--In US placebo-controlled clinical trials for major depressive disorder, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Prozac and in 7% of patients treated with placebo. In US placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with Prozac 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported respectively in 15% and 11% of patients treated with Prozac 60 mg, and in 9% and 5% of patients treated with placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 11 11 Among the most common adverse events associated with discontinuation (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in major depressive disorder) (see Table 3, below). Altered Appetite and Weight--Significant weight loss, especially in underweight depressed or bulimic patients may be an undesirable result of treatment with Prozac. In US placebo-controlled clinical trials for major depressive disorder, 11% of patients treated with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Prozac because of anorexia or weight loss (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Prozac because of anorexia (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac, 60 mg, and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Prozac, 60 mg, on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy. Activation of Mania/Hypomania--In US placebo-controlled clinical trials for major depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Prozac and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of major depressive disorder (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Prozac and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see also Pediatric Use under PRECAUTIONS). Seizures--In US placebo-controlled clinical trials for major depressive disorder, convulsions (or events described as possibly having been seizures) were reported in 0.1% of patients treated with Prozac and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of major depressive disorder. Prozac should be introduced with care in patients with a history of seizures. Suicide--The possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of high risk patients should accompany initial drug therapy. Prescriptions for Prozac should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Because of well-established comorbidity between both OCD and major depressive disorder and bulimia and major depressive disorder, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with OCD or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 12 12 The Long Elimination Half-Lives of Fluoxetine and Its Metabolites--Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Use in Patients With Concomitant Illness--Clinical experience with Prozac in patients with concomitant systemic illness is limited. Caution is advisable in using Prozac in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 312 patients who received Prozac in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose should be used in patients with cirrhosis. Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma (see Renal Disease under CLINICAL PHARMACOLOGY). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE AND ADMINISTRATION). In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred during therapy with Prozac, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with Prozac is instituted or discontinued. Interference With Cognitive and Motor Performance--Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Information for Patients--Physicians are advised to discuss the following issues with patients for whom they prescribe Prozac: Because Prozac may impair judgment, thinking, or motor skills, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected. Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs, or alcohol. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast feeding an infant. Patients should be advised to notify their physician if they develop a rash or hives. Laboratory Tests--There are no specific laboratory tests recommended. Drug Interactions--As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc) is a possibility (see Accumulation and Slow Elimination under CLINICAL PHARMACOLOGY). Drugs Metabolized by P450IID6--Approximately 7% of the normal population has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme P450IID6. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 13 13 Such individuals have been referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and TCAs. Many drugs, such as most drugs effective in the treatment of major depressive disorder, including fluoxetine and other selective uptake inhibitors of serotonin, are metabolized by this isoenzyme; thus, both the pharmacokinetic properties and relative proportion of metabolites are altered in poor metabolizers. However, for fluoxetine and its metabolite the sum of the plasma concentrations of the four active enantiomers is comparable between poor and extensive metabolizers (see Variability in Metabolism under CLINICAL PHARMACOLOGY). Fluoxetine, like other agents that are metabolized by P450IID6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble "poor metabolizers." Therapy with medications that are predominantly metabolized by the P450IID6 system and that have a relatively narrow therapeutic index (see list below), should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of "poor metabolizers." If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by P450IID6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see CONTRAINDICATIONS and WARNINGS). Drugs Metabolized by Cytochrome P450IIIA4--In an in vivo interaction study involving co- administration of fluoxetine with single doses of terfenadine (a cytochrome P450IIIA4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of cytochrome P450IIIA4 activity is not likely to be of clinical significance. CNS Active Drugs--The risk of using Prozac in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Prozac and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see Accumulation and Slow Elimination under CLINICAL PHARMACOLOGY). Anticonvulsants--Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Antipsychotics--Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between serotonin specific reuptake inhibitors (SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. A single case report has suggested possible additive effects of pimozide and fluoxetine leading to bradycardia. For thioridazine, see CONTRAINDICATIONS and WARNINGS. Benzodiazepines--The half-life of concurrently administered diazepam may be prolonged in some patients (see Accumulation and Slow Elimination under Clinical Pharmacology). Co- administration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 14 14 alprazolam levels. Lithium--There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. Tryptophan--Five patients receiving Prozac in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. Monoamine Oxidase Inhibitors--See CONTRAINDICATIONS. Other Drugs Effective in the Treatment of Major Depressive Disorder--In two studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2 to 10-fold when fluoxetine has been administered in combination. This influence may persist for three weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Accumulation and Slow Elimination under CLINICAL PHARMACOLOGY, and Drugs Metabolized by P450IID6 under Drug Interactions). Sumatriptan—There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) is clinically warranted, appropriate observation of the patient is advised. Potential Effects of Co-administration of Drugs Tightly Bound to Plasma Proteins--Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound fluoxetine by other tightly bound drugs (see Accumulation and Slow Elimination under CLINICAL PHARMACOLOGY). Warfarin--Altered anti-coagulant effects, including increased bleeding, have been reported when fluoxetine is co-administered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped. Electroconvulsive Therapy--There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. Carcinogenesis, Mutagenesis, Impairment of Fertility--There is no evidence of carcinogenicity, mutagenicity, or impairment of fertility with Prozac. Carcinogenicity--The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose [MRHD] of 80 mg on a mg/m2 basis), produced no evidence of carcinogenicity. Mutagenicity--Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of Fertility--Two fertility studies conducted in rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse 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 18-936/S-064 Approved Labeling Enclosure Page 15 15 Pregnancy--Pregnancy Category C: In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose [MRHD] of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery--The effect of Prozac on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers--Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. Pediatric Use-- The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18. (see Clinical Trials under CLINICAL PHARMACOLOGY). The efficacy of Prozac for the treatment of OCD was demonstrated in one 13-week placebo- controlled clinical trial with 103 pediatric outpatients ages 7 to <18 (see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in pediatric patients less than 8 years of age in major depressive disorder and less than 7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major depressive disorder or OCD (see Pharmacokinetics under CLINICAL PHARMACOLOGY). The acute adverse event profiles observed in the three studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse event profile observed in the 19-week major depressive disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS). Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the three studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 16 16 pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. Geriatric Use—U.S. fluoxetine clinical trials as of May 8, 1995 (10,782 patients) included 687 patients > 65 years of age and 93 patients > 75 years of age. The efficacy in geriatric patients has been established (see Clinical Trials under CLINICAL PHARMACOLOGY). For pharmacokinetic information in geriatric patients see Age under CLINICAL PHARMACOLOGY. No overall differences in safety or 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. As with other SSRIs, fluoxetine has been associated with cases of clinically significant hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS). Hyponatremia--Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when Prozac was discontinued. Although these cases were complex with varying possible etiologies, some were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted. In two 6-week controlled studies in patients > 60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration was 129 mmol/L. The observed decreases were not clinically significant. Platelet Function--There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking fluoxetine. While there have been reports of abnormal bleeding in several patients taking fluoxetine, it is unclear whether fluoxetine had a causative role. ADVERSE REACTIONS Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered Prozac in panic clinical trials. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 17 17 The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo- Controlled Clinical Trials (excluding data from extensions of trials)--Table 1 enumerates the most common treatment-emergent adverse events associated with the use of Prozac (incidence of at least 5% for Prozac and at least twice that for placebo within at least one of the indications) for the treatment of major depressive disorder, OCD, and bulimia in US controlled clinical trials and panic disorder in US plus non-US controlled trials. Table 2 enumerates treatment-emergent adverse events that occurred in 2% or more patients treated with Prozac and with incidence greater than placebo who participated in US major depressive disorder, OCD, and bulimia controlled clinical trials and US plus non-US panic disorder controlled clinical trials. Table 2 provides combined data for the pool of studies that are provided separately by indication 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 18-936/S-064 Approved Labeling Enclosure Page 18 18 TABLE 1 MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN MAJOR DEPRESSIVE DISORDER, OCD, BULIMIA AND PANIC DISORDER PLACEBO-CONTROLLED CLINICAL TRIALS Percentage of patients reporting event Major Depressive Disorder OCD Bulimia Panic Body System/ Adverse Event Prozac (N=1728) Placebo (N=975) Prozac (N=266) Placebo (N=89) Prozac (N=450) Placebo (N=267) Prozac (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence† 2 -- -- -- 7 -- 1 -- Abnormal ejaculation† -- -- 7 -- 7 -- 2 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. †Denominator used was for males only (N = 690 Prozac major depressive disorder; N = 410 placebo major depressive disorder; N = 116 Prozac OCD; N = 43 placebo OCD; N = 14 Prozac bulimia; N = 1 placebo bulimia; N = 162 Prozac panic; N = 121 placebo panic). --Incidence less than 1%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 19 19 TABLE 2 TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN MAJOR DEPRESSIVE DISORDER, OCD, BULIMIA, and PANIC DISORDER PLACEBO-CONTROLLED CLINICAL TRIALS Percentage of patients reporting event Major Depressive Disorder, OCD, bulimia, and panic disorder combined Body System/ Adverse Event† Prozac (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking Abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. †Included are events reported by at least 2% of patients taking Prozac, except the following events, which had an incidence on placebo ≥ Prozac ( major depressive disorder, OCD, bulimia, and panic disorder combined): abdominal pain, abnormal dreams, accidental injury, back paincough increased, major depressive disorder (includes suicidal thoughts), dysmenorrhea, infection, myalgia, pain, paresthesia, pharyngitis, rhinitis, sinusitis. --Incidence less than 1%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 20 20 Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled clinical trials (excluding data from extensions of trials) --Table 3 lists the adverse events associated with discontinuation of Prozac treatment (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. TABLE 3 MOST COMMON ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION IN MAJOR DEPRESSIVE DISORDER, OCD, BULIMIA AND PANIC DISORDER PLACEBO-CONTROLLED CLINICAL TRIALS Major Depressive Disorder, OCD, bulimia, and panic disorder combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) --Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) -- -- Rash (1%) -- -- Includes US major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 21 21 Other Adverse Events in Pediatric Patients (Children and Adolescents)--Treatment- emergent adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse events was generally similar to that seen in adult studies, as shown in Tables 1 and 2. However, the following adverse events (excluding those which appear in the body or footnotes of Tables 1 and 2 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. The most common adverse event (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in three pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary event associated with discontinuation was collected. Events Observed in Prozac Weekly Clinical Trials—Treatment-emergent adverse events in clinical trials with Prozac Weekly were similar to the adverse events reported by patients in clinical trials with Prozac daily. In a placebo-controlled clinical trial, more patients taking Prozac Weekly reported diarrhea than patients taking placebo (10% vs. 3%, respectively) or taking Prozac 20 mg daily (10% vs. 5%, respectively). Male and Female Sexual Dysfunction with SSRIs--Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US major depressive disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Other Events Observed In Clinical Trials--Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking fluoxetine in US clinical trials as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 1 or 2 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to Prozac use was considered remote; and (4) events occurring in only 1 patient treated with Prozac and which did not have a substantial probability of being acutely life-threatening. Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 22 22 Body as a Whole--Frequent: chest pain, chills; Infrequent: chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: abdominal syndrome acute, hypothermia, intentional injury, neuroleptic malignant syndrome, photosensitivity reaction. Cardiovascular System--Frequent: hemorrhage, hypertension, palpitation; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. Digestive System--Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema. Endocrine System--Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. Hemic and Lymphatic System--Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia. Metabolic and Nutritional--Frequent: weight gain; Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. Musculoskeletal System--Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis. Nervous System--Frequent: agitation, amnesia, confusion, emotional lability, sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder†, psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor. Respiratory System--Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor. Skin and Appendages--Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. Special Senses--Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 23 23 hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect. Urogenital System--Frequent: urinary frequency; Infrequent: abortion‡, albuminuria, amenorrhea‡, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation‡, fibrocystic breast‡, hematuria, leukorrhea‡, menorrhagia‡, metrorrhagia‡, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage‡; Rare: breast engorgement, glycosuria, hypomenorrhea‡, kidney pain, oliguria, priapism‡, uterine hemorrhage‡, uterine fibroids enlarged‡. Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome. † Personality disorder is the COSTART term for designating non-aggressive objectionable behavior. ‡ Adjusted for gender Postintroduction Reports-- Voluntary reports of adverse events temporally associated with Prozac that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors. DRUG ABUSE AND DEPENDENCE Controlled Substance Class--Prozac is not a controlled substance. Physical and Psychological Dependence--Prozac has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Human Experience—Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 24 24 Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all six overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was non-lethal. Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope. Animal Experience--Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among six dogs purposely overdosed with oral fluoxetine, five experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (see Management of Overdose). Management of Overdose--Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 25 25 A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Other Drugs Effective in the Treatment of Major Depressive Disorder under PRECAUTIONS). Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR). DOSAGE AND ADMINISTRATION Major Depressive Disorder-- Initial Treatment— Adult--In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 mg to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in major depressive disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once a day (morning) or b.i.d. schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. Pediatric (Children and Adolescents)--In the, short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of major depressive disorder, patients were administered fluoxetine doses of 10 to 20 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. All Patients--As with other drugs effective in the treatment of major depressive disorder, the full effect may be delayed until 4 weeks of treatment or longer. As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver Disease and Renal Disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation/Extended Treatment--It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Daily Dosing--Systematic evaluation of Prozac has shown that its efficacy in major d i di d i i t i d f i d f t 38 k f ll i 12 k f This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 26 26 label acute treatment (50 weeks total) at a dose of 20 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Weekly Dosing--Systematic evaluation of Prozac Weekly has shown that its efficacy in major depressive disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment with Prozac 20 mg once-daily. However, therapeutic equivalence of Prozac Weekly given on a once-weekly basis with Prozac 20 mg given daily for delaying time to relapse has not been established. (see Clinical Trials under CLINICAL PHARMACOLOGY). Weekly dosing with Prozac Weekly capsule is recommended to be initiated 7 days after the last daily dose of Prozac 20 mg (see CLINICAL PHARMACOLOGY). If satisfactory response is not maintained with Prozac Weekly, consider reestablishing a daily dosing regimen (see Clinical Trials under CLINICAL PHARMACOLOGY). Obsessive-Compulsive Disorder-- Initial Treatment— Adult--In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of obsessive-compulsive disorder, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo (see Clinical Trials under CLINICAL PHARMACOLOGY). In one of these studies, no dose response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once a day (i.e., morning) or b.i.d. schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended, however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. Pediatric (Children and Adolescents)--In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. All Patients--As with the use of Prozac in the treatment of major depressive disorder, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver Disease and Renal Disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 27 27 Maintenance/Continuation Treatment--While there are no systematic studies that answer the question of how long to continue Prozac, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of Prozac after 13 weeks has not been documented in controlled trials, patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. Bulimia Nervosa-- Initial Treatment--In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo (see Clinical Trials under CLINICAL PHARMACOLOGY). Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. As with the use of Prozac in the treatment of major depressive disorder and OCD, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver Disease and Renal Disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment-- Systematic evaluation of continuing Prozac 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking Prozac 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Switching Patients to a Tricyclic Antidepressant (TCA): Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is co-administered or has been recently discontinued (see Other Drugs Effective in the Treatment of Major Depressive Disorder under Drug Interactions). Switching Patients to or from a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping Prozac before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS). Panic Disorder— Initial Treatment—In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of panic disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Treatment should be initiated with a dose of 10 mg/day. After 1 week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 28 28 A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with panic disorder. As with the use of Prozac in other indications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver Disease and Renal Disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment—While there are no systematic studies that answer the question of how long to continue Prozac, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. HOW SUPPLIED The following products are manufactured by Eli Lilly and Company for Dista Products Company. Prozac® Pulvules®, USP, are available in: The 10 mg* Pulvule is opaque green and green, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body: NDC 0777-3104-02 (PU3104) - Bottles of 100 NDC 0777-3104-07 (PU3104) - Bottles of 2000 NDC 0777-3104-82 (PU3104*) - 20 FlexPak§ blister cards of 31 The 20 mg Pulvule is an opaque green cap and off-white body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body: NDC 0777-3105-30 (PU3105) - Bottles of 30 NDC 0777-3105-02 (PU3105) - Bottles of 100 NDC 0777-3105-07 (PU3105) - Bottles of 2000 NDC 0777-3105-33 (PU3105) - (ID†100) Blisters NDC 0777-3105-82 (PU3105*) - 20 FlexPak§ blister cards of 31 The 40 mg Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body: NDC 0777-3107-30 (PU3107*) – Bottles of 30 Liquid, Oral Solution is available in: 20 mg per 5 mL with mint flavor: NDC 0777-5120-58 (MS-5120‡) - Bottles of 120 mL The following products are manufactured and distributed by Eli Lilly and Company. Prozac® Tablets are available in: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-936/S-064 Approved Labeling Enclosure Page 29 29 NDC 0002-4006-30 (TA4006) - Bottles of 30 NDC 0002-4006-02 (TA4006) - Bottles of 100 Prozac WeeklyTM Capsules are available in: The 90 mg* capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with “Lilly” on the cap, and “3004” and “90 mg” on the body. NDC 0002-3004-75 (PU3004) – Blister package of 4 NDC 0002-3004-99 (PU3004) – Blister package of 12 ____________________ Fluoxetine base equivalent. *Protect from light. †Identi-Dose® (unit dose medication, Lilly). ‡Dispense in a tight, light-resistant container. §FlexPak (flexible blister card, Lilly). Store at controlled room temperature, 59° to 86°F (15° to 30°C). ANIMAL TOXICOLOGY Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. Eli Lilly and Company Indianapolis, IN 46285, 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	custom-source	2025-02-12T13:45:03.677607	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/018936s064lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 64}
11,372	1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PROZAC safely and effectively. See full prescribing information for PROZAC. PROZAC (fluoxetine hydrochloride) Pulvules for oral use PROZAC (fluoxetine hydrochloride) oral solution for oral use PROZAC (fluoxetine hydrochloride) delayed-release capsules for oral use Initial U.S. Approval: 1987 WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for Major Depressive Disorder (MDD) and other psychiatric disorders (5.1). When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax. --------------------------- RECENT MAJOR CHANGES ------------------------- Indications and Usage, PROZAC and olanzapine in combination: Depressive Episodes Associated with Bipolar I Disorder (1.5) 03/2009 Treatment Resistant Depression (1.6) 03/2009 Dosage and Administration, PROZAC and olanzapine in combination: Depressive Episodes Associated with Bipolar I Disorder (2. 5) 03/2009 Treatment Resistant Depression (2. 6) 03/2009 Warnings and Precautions: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions (5.2) 01/2009 ------------------------INDICATIONS AND USAGE -------------------------- PROZAC is a selective serotonin reuptake inhibitor indicated for: • Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult and pediatric patients aged 8 to 18 years (1.1) • Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in adult and pediatric patients aged 7-17 years (1.2) • Acute and maintenance treatment of Bulimia Nervosa in adult patients (1.3) • Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients (1.4) PROZAC and olanzapine in combination for: • Acute treatment of Depressive Episodes Associated with Bipolar I Disorder in adults (1.5) • Acute treatment of Treatment Resistant Depression in adults (Major Depressive Disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) (1.6) ----------------------- DOSAGE AND ADMINISTRATION --------------------- Indication Adult Pediatric MDD (2.1) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD (2.2) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa (2.3) 60 mg/day in am - Panic Disorder (2.4) 10 mg/day (initial dose) - Depressive Episodes Associated with Bipolar I Disorder (2.5) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) - Treatment Resistant Depression (2.6) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) - • Consider tapering the dose of fluoxetine for pregnant women during the third trimester (2.7) • A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.7) • Dosing with PROZAC Weekly capsules - initiate 7 days after the last daily dose of PROZAC 20 mg (2.1) PROZAC and olanzapine in combination: • Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability (2.5, 2.6) • Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder or treatment resistant depression (2.5, 2.6) • Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated (2.5, 2.6) ----------------------DOSAGE FORMS AND STRENGTHS -------------------- • Pulvules: 10 mg, 20 mg, 40 mg (3) • Oral solution: 20 mg per 5 ml (3) • Weekly capsules: 90 mg (3) -------------------------------CONTRAINDICATIONS------------------------------ • Do not use with an MAOI or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping PROZAC before treatment with an MAOI (4, 7.1) • Do not use with pimozide due to risk of drug interaction or QTc prolongation (4, 7.9) • Do not use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing PROZAC (4, 7.9) • When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax (4) ------------------------WARNINGS AND PRECAUTIONS ---------------------- • Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1) • Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: Have been reported with PROZAC. Discontinue PROZAC and initiate supportive treatment (5.2) • Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena (5.3) • Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4) • Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.5) • Altered Appetite and Weight: Significant weight loss has occurred (5.6) • Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.7) • Hyponatremia: Has been reported with PROZAC in association with syndrome of inappropriate antidiuretic hormone (SIADH) (5.8) • Anxiety and Insomnia: May occur (5.9) • Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery (5.11) • Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks (5.12) • PROZAC and Olanzapine in Combination: When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax (5.14) -------------------------------ADVERSE REACTIONS ----------------------------- Most common adverse reactions (≥5% and at least twice that for placebo) associated with: Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1) PROZAC and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for Symbyax (6) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ------------------------------- DRUG INTERACTIONS ----------------------------- This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 • Monoamine Oxidase Inhibitors (MAOI): PROZAC is contraindicated for use with MAOI’s, or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping PROZAC before starting treatment with an MAOI (4, 7.1) • Pimozide: PROZAC is contraindicated for use with pimozide due to risk of drug interaction or QTc prolongation (4, 7.9) • Thioridazine: PROZAC is contraindicated for use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing PROZAC (4, 7.9) • Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.9) • Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with PROZAC or when PROZAC has been recently discontinued (7.9) • CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2) • Benzodiazepines: Diazepam – increased t ½ , alprazolam - further psychomotor performance decrement due to increased levels (7.9) • Antipsycotics: Potential for elevation of haloperidol and clozapine levels (7.9) • Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.9) • Serotonergic Drugs: Potential for Serotonin Syndrome (5.2, 7.3) • Triptans: There have been rare postmarketing reports of Serotonin Syndrome with use of an SSRI and a triptan (5.2, 7.4) • Tryptophan: Concomitant use with tryptophan is not recommended (5.2, 7.5) • Drugs that Interfere with Hemostasis (e.g. NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding (7.6) • Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations (7.8, 7.9) • Olanzapine: When used in combination with PROZAC, also refer to the Drug Interactions section of the package insert for Symbyax (7.9) ------------------------USE IN SPECIFIC POPULATIONS---------------------- • Pregnancy: PROZAC should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus (8.1) • Nursing Mothers: Breast feeding is not recommended (8.3) • Pediatric Use: Safety and effectiveness of PROZAC and olanzapine in combination have not been established in patients less than 18 years of age (8.4) • Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis (8.6) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: [00/0000] FULL PRESCRIBING INFORMATION: CONTENTS* 6.2 Other Reactions WARNING — SUICIDALITY AND ANTIDEPRESSANT DRUGS 6.3 Postmarketing Experience 1 INDICATIONS AND USAGE 7 DRUG INTERACTIONS 1.1 Major Depressive Disorder 7.1 Monoamine Oxidase Inhibitors 1.2 Obsessive Compulsive Disorder 7.2 CNS Acting Drugs 1.3 Bulimia Nervosa 7.3 Serotonergic Drugs 1.4 Panic Disorder 7.4 Triptans 1.5 PROZAC and Olanzapine in Combination: Depressive Episodes 7.5 Tryptophan Associated with Bipolar I Disorder 7.6 Drugs that Interfere with Hemostasis (e.g. NSAIDS, Aspirin, 1.6 PROZAC and Olanzapine in Combination: Treatment Resistant Warfarin) Depression 7.7 Electroconvulsive Therapy (ECT) 7.8 Potential for Other Drugs to affect PROZAC 2 DOSAGE AND ADMINISTRATION 7.9 Potential for PROZAC to affect Other Drugs 2.1 Major Depressive Disorder 2.2 Obsessive Compulsive Disorder 8 USE IN SPECIFIC POPULATIONS 2.3 Bulimia Nervosa 8.1 Pregnancy 2.4 Panic Disorder 8.2 Labor and Delivery 2.5 PROZAC and Olanzapine in Combination: Depressive Episodes 8.3 Nursing Mothers associated with Bipolar I Disorder 8.4 Pediatric Use 2.6 PROZAC and Olanzapine in Combination: Treatment Resistant 8.5 Geriatric Use Depression 8.6 Hepatic Impairment 2.7 Dosing in Specific Populations 9 DRUG ABUSE AND DEPENDENCE 2.8 Discontinuation of Treatment 9.3 Dependence 3 DOSAGE FORMS AND STRENGTHS 10 OVERDOSAGE 4 CONTRAINDICATIONS 10.1 Human Experience 10.2 Animal Experience 5 WARNINGS AND PRECAUTIONS 10.3 Management of Overdose 5.1 Clinical Worsening and Suicide Risk 5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome 11 DESCRIPTION (NMS)-like Reactions 12 CLINICAL PHARMACOLOGY 5.3 Allergic Reactions and Rash 12.1 Mechanism of Action 5.4 Screening Patients for Bipolar Disorder and Monitoring for 12.2 Pharmacodynamics Mania/Hypomania 12.3 Pharmacokinetics 5.5 Seizures 12.4 Specific Populations 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.6 Altered Appetite and Weight 13.2 Animal Toxicology and/or Pharmacology 5.7 Abnormal Bleeding 5.8 Hyponatremia 14 CLINICAL STUDIES 5.9 Anxiety and Insomnia 14.1 Major Depressive Disorder 5.10 Use in Patients with Concomitant Illness 14.2 Obsessive Compulsive Disorder 5.11 Potential for Cognitive and Motor Impairment 14.3 Bulimia Nervosa 5.12 Long Elimination Half-Life 14.4 Panic Disorder 5.13 Discontinuation of Treatment 16 HOW SUPPLIED/STORAGE AND HANDLING 5.14 PROZAC and olanzapine in Combination 16.1 How Supplied 6 ADVERSE REACTIONS 16.2 Storage and Handling 6.1 Clinical Trials Experience 17 PATIENT COUNSELING INFORMATION This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 17.1 General Information 17.8 Use of Concomitant Medications 17.2 Clinical Worsening and Suicide Risk 17.9 Discontinuation of Treatment 17.3 Serotonin Syndrome or Neuroleptic Malignant Syndrome 17.10 Use in Specific Populations (NMS)-like Reactions 17.4 17.5 17.6 Allergic Reactions and Rash Abnormal Bleeding Hyponatremia *Sections or subsections omitted from the full prescribing information are not listed 17.7 Potential for Cognitive and Motor Impairment 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 30 35 40 45 50 55 4 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 33 34 36 37 38 39 41 42 43 44 46 47 48 49 51 52 53 54 56 FULL PRESCRIBING INFORMATION WARNING: 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 PROZAC 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. PROZAC is approved for use in pediatric patients with MDD and Obsessive Compulsive Disorder (OCD) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax. 1 INDICATIONS AND USAGE 1.1 Major Depressive Disorder PROZAC® is indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to18 years [see Clinical Studies (14.1)]. The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods, should periodically be re evaluated [see Dosage and Administration (2.1)]. 1.2 Obsessive Compulsive Disorder PROZAC is indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2)]. The effectiveness of PROZAC in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use PROZAC for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.2)]. 1.3 Bulimia Nervosa PROZAC is indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)]. The physician who elects to use PROZAC for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)]. 1.4 Panic Disorder PROZAC is indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [see Clinical Studies (14.4)]. The effectiveness of PROZAC in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use PROZAC for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.4)]. 1.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax® . PROZAC and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder in adult patients. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. 1.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. PROZAC and olanzapine in combination is indicated for the acute treatment of treatment resistant depression (Major Depressive Disorder in adult patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode). PROZAC monotherapy is not indicated for the treatment of treatment resistant depression. 2 DOSAGE AND ADMINISTRATION 2.1 Major Depressive Disorder Initial Treatment Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 57 satisfactory response in Major Depressive Disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is 58 recommended as the initial dose. 59 A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 60 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a 61 maximum dose of 80 mg/day. 62 Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its 63 effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day 64 [see Clinical Studies (14.1)]. Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose 65 should be increased to 20 mg/day. 66 However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A 67 dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. 68 All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed 69 until 4 weeks of treatment or longer. 70 Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of Major Depressive Disorder 71 require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the 72 dose needed to maintain and/or sustain euthymia is unknown. 73 Daily Dosing — Systematic evaluation of PROZAC in adult patients has shown that its efficacy in Major Depressive Disorder 74 is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day 75 [see Clinical Studies (14.1)]. 76 Weekly Dosing — Systematic evaluation of PROZAC® Weekly™ in adult patients has shown that its efficacy in Major 77 Depressive Disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment 78 with PROZAC 20 mg once daily. However, therapeutic equivalence of PROZAC Weekly given on a once-weekly basis with 79 PROZAC 20 mg given daily for delaying time to relapse has not been established [see Clinical Studies (14.1)]. 80 Weekly dosing with PROZAC Weekly capsules is recommended to be initiated 7 days after the last daily dose of PROZAC 81 20 mg [see Clinical Pharmacology (12.3)]. 82 If satisfactory response is not maintained with PROZAC Weekly, consider reestablishing a daily dosing regimen [see Clinical 83 Studies (14.1)]. 84 Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA 85 concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Drug 86 Interactions (7.9)]. 87 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) — At least 14 days should elapse between 88 discontinuation of an MAOI and initiation of therapy with PROZAC. In addition, at least 5 weeks, perhaps longer, should be allowed 89 after stopping PROZAC before starting an MAOI [see Contraindications (4) and Drug Interactions (7.1)]. 90 2.2 Obsessive Compulsive Disorder 91 Initial Treatment 92 Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were 93 administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these studies, no 94 dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is 95 recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second 96 study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic 97 effect may be delayed until 5 weeks of treatment or longer. 98 Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose 99 range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The 100 maximum fluoxetine dose should not exceed 80 mg/day. 101 Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the 102 treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)]. 103 In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose 104 should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical 105 improvement is observed. A dose range of 20 to 60 mg/day is recommended. 106 In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered 107 after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. 108 Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. 109 Maintenance/Continuation Treatment) — While there are no systematic studies that answer the question of how long to 110 continue PROZAC, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the 111 efficacy of PROZAC after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under 112 double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to 113 maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. 114 2.3 Bulimia Nervosa 115 Initial Treatment) — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia 116 Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo [see Clinical Studies (14.3)]. Only the 60 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. Maintenance/Continuation Treatment) — Systematic evaluation of continuing PROZAC 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking PROZAC 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment [see Clinical Studies (14.3)]. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. 2. 4 Panic Disorder Initial Treatment) — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.4)]. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. Maintenance/Continuation Treatment) — While there are no systematic studies that answer the question of how long to continue PROZAC, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. 2.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. Table 1: Approximate Dose Correspondence Between Symbyax1 and the Combination of PROZAC and Olanzapine 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 1 Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of PROZAC and olanzapine. While there is no body of evidence to answer the question of how long a patient treated with PROZAC and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. 2.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 20 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. While there is no body of evidence to answer the question of how long a patient treated with PROZAC and olanzapine in combination should remain on it, it is generally accepted that treatment resistant depression (Major Depressive Disorder in adult For Symbyax (mg/day) Use in Combination Olanzapine (mg/day) PROZAC (mg/day) 3 mg olanzapine/25 mg fluoxetine 2.5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. PROZAC monotherapy is not indicated for the treatment of treatment resistant depression (Major Depressive Disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode) have not been established. 2.7 Dosing in Specific Populations Treatment of pregnant Women During the Third Trimester) — When treating pregnant women with PROZAC during the third trimester, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. The physician may consider tapering PROZAC in the third trimester [see Use in Specific Populations (8.1)]. Geriatrics) — A lower or less frequent dosage should be considered for the elderly [see Use in Specific Populations (8.5)] Hepatic Impairment) — As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment [see Clinical Pharmacology (12.4) and Use in Specific Populations (8.6)]. Concomitant Illness ) — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology (12.4) and Warnings and Precautions (5.10)]. PROZAC and Olanzapine in Combination) — The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modifications may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. PROZAC and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 18 years of age [see Warnings and Precautions (5.14) and Drug Interactions (7.9)]. 2.8 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.13)]. 3 DOSAGE FORMS AND STRENGTHS • 10 mg Pulvule is an opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body • 20 mg Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body • 40 mg Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body • 20 mg per 5 mL Liquid, Oral Solution with mint flavor • 90 mg Prozac Weekly™ Capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body 4 CONTRAINDICATIONS When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. The use of PROZAC is contraindicated with the following: • Monoamine Oxidase Inhibitors [see Drug Interactions (7.1)] • Pimozide [see Drug Interactions (7.9)] • Thioridazine [see Drug Interactions (7.9)] 5 WARNINGS AND PRECAUTIONS When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. 5.1 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 227 pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials 228 (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of 229 suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences 230 in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences 231 (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo 232 difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2. 233 234 Table 2: Suicidality per 1000 Patients Treated 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 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 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. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.13)]. 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 PROZAC should be written for the smallest quantity of capsules, or liquid consistent with good patient management, in order to reduce the risk of overdose. It should be noted that PROZAC is approved in the pediatric population only for Major Depressive Disorder and Obsessive Compulsive Disorder. Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 18 years of age have not been established. 5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including PROZAC treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS- like signs and symptoms. The concomitant use of PROZAC with MAOIs intended to treat depression is contraindicated [see Contraindications (4) and Drug Interactions (7.1)]. If concomitant treatment of PROZAC with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions (7.4)]. The concomitant use of PROZAC with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions (7.3)]. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 279 Treatment with PROZAC and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be 280 discontinued immediately if the above reactions occur, and supportive symptomatic treatment should be initiated. 281 5.3 Allergic Reactions and Rash 282 In US fluoxetine clinical trials as of May 8, 1995, 7% of 10,782 patients developed various types of rashes and/or urticaria. 283 Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment 284 because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash 285 include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild 286 transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with 287 antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely. 288 In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient 289 was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating 290 syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes 291 suggestive of serum sickness. 292 Since the introduction of PROZAC, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have 293 developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has 294 been reported to occur in association with these systemic reactions. 295 Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have 296 been reported. 297 Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. 298 These reactions have occurred with dyspnea as the only preceding symptom. 299 Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic 300 processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the 301 appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, PROZAC should be 302 discontinued. 303 5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 304 A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established 305 in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a 306 mixed/manic episode in patients at risk for Bipolar Disorder. Whether any of the symptoms described for clinical worsening and 307 suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with 308 depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should 309 include a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression. It should be noted that 310 PROZAC and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder 311 [see Warnings and Precautions section of the package insert for Symbyax]. PROZAC monotherapy is not indicated for the treatment 312 of depressive episodes associated with Bipolar I Disorder. 313 In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients 314 treated with PROZAC and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small 315 proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive 316 Disorder [see Use in Specific Populations (8.4)]. 317 In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with PROZAC 318 and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In all 319 US PROZAC clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations 320 (8.4)]. 321 5.5 Seizures 322 In US placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having 323 been seizures) were reported in 0.1% of patients treated with PROZAC and 0.2% of patients treated with placebo. No patients reported 324 convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In all US PROZAC clinical trials as of May 8, 1995, 325 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs 326 effective in the treatment of Major Depressive Disorder. PROZAC should be introduced with care in patients with a history of 327 seizures. 328 5.6 Altered Appetite and Weight 329 Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment 330 with PROZAC. 331 In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with PROZAC and 2% of 332 patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with 333 PROZAC and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with PROZAC 334 because of anorexia or weight loss [see Use in Specific Populations (8.4)]. 335 In US placebo-controlled clinical trials for OCD, 17% of patients treated with PROZAC and 10% of patients treated with 336 placebo reported anorexia (decreased appetite). One patient discontinued treatment with PROZAC because of anorexia [see Use in 337 Specific Populations (8.4)]. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 338 In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with PROZAC 60 mg and 4% of patients 339 treated with placebo reported anorexia (decreased appetite). Patients treated with PROZAC 60 mg on average lost 0.45 kg compared 340 with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during 341 therapy. 342 5.7 Abnormal Bleeding 343 SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal 344 anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case 345 control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the 346 occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, 347 hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding 348 associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug 349 Interactions (7.6)]. 350 5.8 Hyponatremia 351 Hyponatremia has been reported during treatment with SNRIs and SSRIs, including PROZAC. In many cases, this 352 hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum 353 sodium lower than 110 mmol/L have been reported and appeared to be reversible when PROZAC was discontinued. Elderly patients 354 may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume 355 depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of PROZAC should be considered in patients 356 with symptomatic hyponatremia and appropriate medical intervention should be instituted. 357 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, 358 and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, 359 coma, respiratory arrest, and death. 360 5.9 Anxiety and Insomnia 361 In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with PROZAC and 7% 362 to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. 363 In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with PROZAC and in 22% 364 of patients treated with placebo. Anxiety was reported in 14% of patients treated with PROZAC and in 7% of patients treated with 365 placebo. 366 In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with PROZAC 367 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients 368 treated with PROZAC 60 mg and in 9% and 5% of patients treated with placebo. 369 Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at 370 least 1% for PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled 371 fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness 372 (1% in Major Depressive Disorder) [see Table 5]. 373 5.10 Use in Patients with Concomitant Illness 374 Clinical experience with PROZAC in patients with concomitant systemic illness is limited. Caution is advisable in using 375 PROZAC in patients with diseases or conditions that could affect metabolism or hemodynamic responses. 376 Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of 377 myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies 378 during the product’s premarket testing. However, the electrocardiograms of 312 patients who received PROZAC in double-blind trials 379 were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was 380 reduced by approximately 3 beats/min. 381 Glycemic Control — In patients with diabetes, PROZAC may alter glycemic control. Hypoglycemia has occurred during 382 therapy with PROZAC, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of 383 medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted 384 when therapy with PROZAC is instituted or discontinued. 385 5.11 Potential for Cognitive and Motor Impairment 386 As with any CNS-active drug, PROZAC has the potential to impair judgment, thinking, or motor skills. Patients should be 387 cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does 388 not affect them adversely. 389 5.12 Long Elimination Half-Life 390 Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully 391 reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of 392 potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and 393 norfluoxetine following the discontinuation of fluoxetine [see Clinical Pharmacology (12.3)]. 394 5.13 Discontinuation of Treatment 395 During marketing of PROZAC, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon 396 discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 397 sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, 398 insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation 399 symptoms. Patients should be monitored for these symptoms when discontinuing treatment with PROZAC. A gradual reduction in the 400 dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose 401 or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician 402 may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at 403 the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. 404 5.14 PROZAC and Olanzapine in Combination 405 When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package 406 insert for Symbyax. 407 6 ADVERSE REACTIONS 408 When using PROZAC and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for 409 Symbyax. 410 6.1 Clinical Trials Experience 411 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 412 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in 413 practice. 414 Multiple doses of PROZAC had been administered to 10,782 patients with various diagnoses in US clinical trials as of 415 May 8, 1995. In addition, there have been 425 patients administered PROZAC in panic clinical trials. Adverse reactions were recorded 416 by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful 417 estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited 418 (i.e., reduced) number of standardized reaction categories. 419 In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse 420 reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse 421 reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving 422 therapy following baseline evaluation. It is important to emphasize that reactions reported during therapy were not necessarily caused 423 by it. 424 The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side 425 effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the 426 clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving 427 different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for 428 estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. 429 Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding 430 data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use 431 of PROZAC (incidence of at least 5% for PROZAC and at least twice that for placebo within at least 1 of the indications) for the 432 treatment of Major Depressive Disorder, OCD, and bulimia in US controlled clinical trials and Panic Disorder in US plus non-US 433 controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with PROZAC 434 and with incidence greater than placebo who participated in US Major Depressive Disorder, OCD, and bulimia controlled clinical 435 trials and US plus non-US Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are 436 provided separately by indication in Table 3. 437 438 Table 3: Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, 439 and Panic Disorder Placebo-Controlled Clinical Trials1,2 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Reaction PROZAC (N=1728) Placebo (N=975) PROZAC (N=266) Placebo (N=89) PROZAC (N=450) Placebo (N=267) PROZAC (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence3 2 -- -- -- 7 -- 1 -- Abnormal ejaculation3 -- -- 7 -- 7 -- 2 1 440 1 Incidence less than 1%. 441 2 Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic 442 Disorder clinical trials. 443 3 Denominator used was for males only (N=690 PROZAC Major Depressive Disorder; N=410 placebo Major Depressive Disorder; 444 N=116 PROZAC OCD; N=43 placebo OCD; N=14 PROZAC bulimia; N=1 placebo bulimia; N=162 PROZAC panic; N=121 445 placebo panic). 446 447 Table 4: Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic 448 Disorder Placebo-Controlled Clinical Trials1,2 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Reaction PROZAC (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 449 1 Incidence less than 1%. 450 2 Includes US data for Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US data for Panic 451 Disorder clinical trials. 452 453 Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled 454 clinical trials (excluding data from extensions of trials) — Table 5 lists the adverse reactions associated with discontinuation of 455 PROZAC treatment (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary 456 reaction associated with discontinuation) in Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US 457 Panic Disorder clinical trials. 458 459 Table 5: Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and 460 Panic Disorder Placebo-Controlled Clinical Trials1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) -- -- Rash (1%) -- -- 461 1 Includes US Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical 462 trials. 463 464 Other adverse reactions in pediatric patients (children and adolescents) — Treatment-emergent adverse reactions were 465 collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally 466 similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which 467 appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were 468 reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, 469 epistaxis, urinary frequency, and menorrhagia. 470 The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with 471 discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was 472 mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with 473 discontinuation was collected. 474 Reactions observed in PROZAC Weekly clinical trials — Treatment-emergent adverse reactions in clinical trials with 475 PROZAC Weekly were similar to the adverse reactions reported by patients in clinical trials with PROZAC daily. In a 476 placebo-controlled clinical trial, more patients taking PROZAC Weekly reported diarrhea than patients taking placebo 477 (10% versus 3%, respectively) or taking PROZAC 20 mg daily (10% versus 5%, respectively). 478 Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual 479 satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 480 particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and 481 severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part 482 because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual 483 experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in 484 US Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect 485 reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women 486 taking fluoxetine of orgasmic dysfunction, including anorgasmia. 487 There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. 488 Priapism has been reported with all SSRIs. 489 While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should 490 routinely inquire about such possible side effects. 491 6.2 Other Reactions 492 Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This 493 listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was 494 remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or 495 (5) which occurred at a rate equal to or less than placebo. 496 Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at 497 least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in 498 fewer than 1/1000 patients. 499 Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity 500 reaction. 501 Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia. 502 Digestive System — Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal 503 ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage. 504 Hemic and Lymphatic System — Infrequent: ecchymosis; Rare: petechia, purpura. 505 Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, buccoglossal syndrome, euphoria, hypertonia, 506 libido increased, myoclonus, paranoid reaction; Rare: delusions. 507 Respiratory System —Rare: larynx edema. 508 Skin and Appendages — Rare: purpuric rash. 509 Special Senses — Frequent: taste perversion; Infrequent: mydriasis. 510 6. 3 Postmarketing Experience 511 The following adverse reactions have been identified during post approval use of PROZAC. Because these reactions are 512 reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal 513 relationship to drug exposure. 514 Voluntary reports of adverse reactions temporally associated with PROZAC that have been received since market introduction 515 and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation1, cataract, 516 cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome 517 with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which 518 completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, 519 erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest1, hepatic failure/necrosis, 520 hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, movement disorders developing in patients with 521 risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, 522 pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, 523 thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including torsades de pointes–type arrhythmias), and vaginal 524 bleeding, and violent behaviors1. 1 525 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. 526 7 DRUG INTERACTIONS 527 As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug 528 inhibition or enhancement, etc.) is a possibility. 529 7.1 Monoamine Oxidase Inhibitors (MAOI) 530 There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic 531 instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to 532 delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who 533 have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic 534 malignant syndrome. Therefore, PROZAC should not be used in combination with an MAOI, or within a minimum of 14 days of 535 discontinuing therapy with an MAOI [see Contraindications (4)]. Since fluoxetine and its major metabolite have very long 536 elimination half-lives, at least 5 weeks perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses 537 should be allowed after stopping PROZAC before starting an MAOI [see Clinical Pharmacology (12.3)]. 538 7.2 CNS Acting Drugs This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 539 Caution is advised if the concomitant administration of PROZAC and such drugs is required. In evaluating individual cases, 540 consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration 541 schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)]. 542 7.3 Serotonergic Drugs 543 Based on the mechanism of action of SNRIs and SSRIs, including PROZAC, and the potential for serotonin syndrome, 544 caution is advised when PROZAC is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such 545 as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort [see Warnings 546 and Precautions (5.2)]. The concomitant use of PROZAC with SNRIs, SSRIs, or tryptophan is not recommended [see Drug 547 Interactions (7.4), (7.5)]. 548 7.4 Triptans 549 There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment 550 of PROZAC with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation 551 and dose increases [see Warnings and Precautions (5.2) and Drug Interactions (7.3)]. 552 7.5 Tryptophan 553 Five patients receiving PROZAC in combination with tryptophan experienced adverse reactions, including agitation, 554 restlessness, and gastrointestinal distress. The concomitant use with tryptophan is not recommended [see Warnings and Precautions 555 (5.2) and Drug Interactions (7.3)]. 556 7.6 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) 557 Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort 558 design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the 559 occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of 560 bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered 561 with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see 562 Warnings and Precautions (5.7)]. 563 7.7 Electroconvulsive Therapy (ECT) 564 There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports 565 of prolonged seizures in patients on fluoxetine receiving ECT treatment. 566 7.8 Potential for Other Drugs to affect PROZAC 567 Drugs Tightly Bound to Plasma Proteins – Because fluoxetine is tightly bound to plasma protein, adverse effects may result 568 from displacement of protein-bound fluoxetine by other tightly-bound drugs [see Clinical Pharmacology (12.3)]. 569 7.9 Potential for PROZAC to affect Other Drugs 570 Pimozide – Concomitant use in patients taking pimozide is contraindicated. Clinical studies of pimozide with other 571 antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine 572 has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and 573 PROZAC [see Contraindications (4)]. 574 Thioridazine – Thioridazine should not be administered with PROZAC or within a minimum of 5 weeks after PROZAC has 575 been discontinued [see Contraindications (4)]. 576 In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral 577 dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared 578 with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, 579 this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels 580 of thioridazine. 581 Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious 582 ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with 583 fluoxetine-induced inhibition of thioridazine metabolism. 584 Drugs Metabolized by CYP2D6 – Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal 585 CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by 586 CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics 587 (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly 588 metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low 589 end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing 590 requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug 591 metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow 592 therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious 593 ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be 594 administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4)]. 595 Tricyclic Antidepressants (TCAs) — In 2 studies, previously stable plasma levels of imipramine and desipramine have 596 increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 597 longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to 598 be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Clinical Pharmacology (12.3)]. 599 Benzodiazapines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical 600 Pharmacology (12.3)]. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and 601 in further psychomotor performance decrement due to increased alprazolam levels. 602 Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs 603 and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant 604 fluoxetine. [see Contraindications (4)]. 605 Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant 606 concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. 607 Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with 608 fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when 609 these drugs are administered concomitantly. 610 Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma protein, the administration of 611 fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma 612 concentrations potentially resulting in an adverse effect. [see Clinical Pharmacology (12.3)]. 613 Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of 614 terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. 615 Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more 616 potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, 617 cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical 618 significance. 619 Olanzapine— Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the 620 maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this 621 factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely 622 recommended. 623 When using PROZAC and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for 624 Symbyax. 625 8 USE IN SPECIFIC POPULATIONS 626 When using PROZAC and olanzapine in combination, also refer to the Use in Specific Populations section of the package 627 insert for Symbyax. 628 8.1 Pregnancy 629 Teratogenic Effects 630 Pregnancy Category C — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity 631 following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a 632 mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, 633 and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the 634 maximum recommended human dose (MRHD) on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a 635 mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats 636 treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a 637 mg/m2 basis). PROZAC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 638 Treatment of Pregnant Women During the Third Trimester — Neonates exposed to PROZAC, SNRIs, or SSRIs, late in the 639 third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such 640 complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, 641 seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, 642 irritability, and constant crying. These features are consistent with either a direct toxic effect of SNRIs and SSRIs or, possibly, a drug 643 discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. 644 Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn 645 (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity 646 and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants 647 were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week 648 of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative 649 evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the 650 potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels 651 of PPHN risk. 652 When treating pregnant women with PROZAC during the third trimester, the physician should carefully consider both the 653 potential risks and potential benefits of treatment. Physicians should note that in a prospective longitudinal study of 201 women with a 654 history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication 655 during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. 656 The physician may consider tapering PROZAC in the third trimester. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 657 8.2 Labor and Delivery 658 The effect of PROZAC on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and 659 because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and 660 delivery only if the potential benefit justifies the potential risk to the fetus. 661 8.3 Nursing Mothers 662 Because PROZAC is excreted in human milk, nursing while on PROZAC is not recommended. In one breast-milk sample, the 663 concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No 664 adverse effects on the infant were reported. In another case, an infant nursed by a mother on PROZAC developed crying, sleep 665 disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of 666 norfluoxetine on the second day of feeding. 667 8.4 Pediatric Use 668 The efficacy of PROZAC for the treatment of Major Depressive Disorder was demonstrated in two 8- to 9-week 669 placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 [see Clinical Studies (14.1)]. 670 The efficacy of PROZAC for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 671 103 pediatric outpatients ages 7 to <18 [see Clinical Studies (14.2)]. 672 The safety and effectiveness in pediatric patients <8 years of age in Major Depressive Disorder and <7 years of age in OCD 673 have not been established. 674 Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with Major Depressive Disorder or OCD 675 [see Clinical Pharmacology (12.3)]. 676 The acute adverse reaction profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) 677 were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 678 19-week Major Depressive Disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that 679 observed in adult trials with fluoxetine [see Adverse Reactions (6.1)]. 680 Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) 681 fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) 682 fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of 683 mania/hypomania is recommended. 684 As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and 685 adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 686 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with 687 a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed 688 for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term 689 effects of fluoxetine on the growth, development and maturation of children and adolescent patients. Therefore, height and weight 690 should be monitored periodically in pediatric patients receiving fluoxetine. [see Warnings and Precautions (5.6)]. 691 PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions 692 (5.1)]. Anyone considering the use of PROZAC in a child or adolescent must balance the potential risks with the clinical need. 693 Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone 694 development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically 695 relevant exposures. 696 In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) 697 through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur 698 length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels 699 of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and 700 reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal 701 vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks 702 after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and 703 reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, 704 testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that 705 the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage 706 was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been 707 reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, 708 intermediate, and high dose in this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in 709 pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, 710 norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 times, respectively, pediatric exposure at the MRD. 711 A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile 712 period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone 713 formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body 714 weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for 715 pediatric patients on a body surface area (mg/m2) basis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 716 In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal 717 Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increase shock 718 avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a 719 mg/m2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in 720 humans is uncertain. 721 Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 18 years of age have not been 722 established. 723 8.5 Geriatric Use 724 US fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric 725 patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical 726 Pharmacology (12.4)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 727 and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater 728 sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including fluoxetine, have been associated with cases of 729 clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and 730 Precautions (5.8)]. 731 Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to 732 determine whether they respond differently from younger patients. 733 8.6 Hepatic Impairment 734 In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, 735 thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients 736 with cirrhosis. Caution is advised when using PROZAC in patients with diseases or conditions that could affect its metabolism [see 737 Dosage and Administration (2.7) and Clinical Pharmacology (12.4)]. 738 9 DRUG ABUSE AND DEPENDENCE 739 9.3 Dependence 740 PROZAC has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical 741 dependence. While the premarketing clinical experience with PROZAC did not reveal any tendency for a withdrawal syndrome or any 742 drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience 743 the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should 744 carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of 745 PROZAC (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). 746 10 OVERDOSAGE 747 10.1 Human Experience 748 Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of 749 overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. 750 Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely 751 recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, 752 unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and 753 hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal 754 overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in 755 adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who 756 took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. 757 Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in 758 combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients 759 had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, 760 attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to 761 clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in 762 children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. 763 Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, 764 ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), 765 hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope. 766 10.2 Animal Experience 767 Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, 768 animal experiments can provide useful insights into possible treatment strategies. 769 The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses 770 produced hyperirritability and convulsions in several animal species. 771 Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately 772 upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma 773 concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, 774 chronically. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 775 In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or 776 QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac 777 toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see Overdosage (10.3)]. 778 10.3 Management of Overdose 779 Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the 780 treatment of Major Depressive Disorder. 781 Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and 782 symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric 783 tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. 784 Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, 785 hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. 786 A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of 787 a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically 788 significant sequelae and extend the time needed for close medical observation [see Drug Interactions (7. 9)]. 789 Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit 790 spontaneously may respond to diazepam. 791 In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a 792 poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control 793 centers are listed in the Physicians’ Desk Reference (PDR). 794 For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of 795 the Symbyax package insert. 796 11 DESCRIPTION 797 PROZAC® (fluoxetine capsules, USP and fluoxetine oral solution, USP) is a selective serotonin reuptake inhibitor for oral 798 administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is 799 designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of 800 C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: Chemical Stru cture 801 Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. 802 Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol), 20 mg (64.7 µmol), or 40 mg (129.3 µmol) 803 of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- 804 and 20 mg Pulvules also contain FD&C Blue No. 1, and the 40 mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. 805 The oral solution contains fluoxetine hydrochloride equivalent to 20 mg per 5 mL (64.7 µmol) of fluoxetine. It also contains 806 alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. 807 PROZAC Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride 808 equivalent to 90 mg (291 µmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, 809 hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and 810 other inactive ingredients. 811 12 CLINICAL PHARMACOLOGY 812 12.1 Mechanism of Action 813 Although the exact mechanism of Prozac is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin 814 12.2 Pharmacodynamics 815 Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human 816 platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. 817 Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various 818 anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and 819 other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. 820 12.3 Pharmacokinetics 821 Systemic Bioavailability — In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 822 55 ng/mL are observed after 6 to 8 hours. 823 The Pulvule, oral solution, and PROZAC Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear 824 to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not 825 clinically significant. Thus, fluoxetine may be administered with or without food. PROZAC Weekly capsules, a delayed-release This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 826 formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the 827 pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release 828 formulations. 829 Protein Binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound 830 in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly 831 protein-bound drugs has not been fully evaluated, but may be important. 832 Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both 833 enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine 834 enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. 835 Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified 836 metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, 837 S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. 838 R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination 839 appears to be hepatic metabolism to inactive metabolites excreted by the kidney. 840 Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme 841 cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, 842 dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these 843 individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, 844 concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears 845 normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active 846 enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the 847 same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine 848 achieves a steady-state concentration rather than increasing without limit. 849 Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin 850 reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system 851 (such as the TCAs) may lead to drug interactions [see Drug Interactions (7.9)]. 852 Accumulation and Slow Elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after 853 acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 854 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed 855 attainment of steady state, even when a fixed dose is used [see Warnings and Precautions (5.12)]. After 30 days of dosing at 856 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL 857 have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s 858 metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life 859 after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels 860 seen at 4 to 5 weeks. 861 The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance 862 will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of 863 previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are 864 prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of PROZAC. 865 Weekly Dosing — Administration of PROZAC Weekly once weekly results in increased fluctuation between peak and trough 866 concentrations of fluoxetine and norfluoxetine compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and 867 for norfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of clinical response. Peak 868 concentrations from once-weekly doses of PROZAC Weekly capsules of fluoxetine are in the range of the average concentration for 869 20 mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the 870 concentrations maintained by 20 mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly 871 dosing are in relative proportion to the total dose administered. Average steady-state fluoxetine concentrations are approximately 872 50% lower following the once-weekly regimen compared with the once-daily regimen. 873 Cmax for fluoxetine following the 90 mg dose was approximately 1.7-fold higher than the Cmax value for the established 20 mg 874 once-daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90 mg once-weekly dose 875 and the last 20 mg once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient increase in the 876 average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a 877 pharmacokinetic perspective, it may be better to separate the first 90 mg weekly dose and the last 20 mg once-daily dose by 1 week 878 [see Dosage and Administration (2.1)]. 879 12.4 Specific Populations 880 Liver Disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of 881 fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared 882 with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration 883 of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in 884 patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less 885 frequent dose should be used [see Dosage and Administration (2.7), Use in Specific Populations (8.6)]. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 886 Renal Disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months 887 produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal 888 function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with 889 severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. 890 Geriatric Pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did 891 not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a 892 single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have 893 systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have 894 been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 895 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual 896 age-associated pattern of adverse reactions was observed in those elderly patients. 897 Pediatric Pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric 898 patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with Major Depressive Disorder or Obsessive 899 Compulsive Disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of 900 fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine 901 steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These 902 differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics 903 was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric 904 patients (ages 8 to <18) diagnosed with Major Depressive Disorder. 905 Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, 906 these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and 907 norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks 908 of daily dosing. 909 13 NONCLINICAL TOXICOLOGY 910 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 911 Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 912 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 913 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity. 914 Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following 915 assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid 916 exchange assay in Chinese hamster bone marrow cells. 917 Impairment of Fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day 918 (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility. However, 919 adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)]. 920 13.2 Animal Toxicology and/or Pharmacology 921 Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after 922 cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, 923 including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. 924 14 CLINICAL STUDIES 925 When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for 926 Symbyax. 927 14.1 Major Depressive Disorder 928 Daily Dosing 929 Adult — The efficacy of PROZAC was studied in 5- and 6-week placebo-controlled trials with depressed adult and geriatric 930 outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of Major 931 Depressive Disorder. PROZAC was shown to be significantly more effective than placebo as measured by the Hamilton Depression 932 Rating Scale (HAM-D). PROZAC was also significantly more effective than placebo on the HAM-D subscores for depressed mood, 933 sleep disturbance, and the anxiety subfactor. 934 Two 6-week controlled studies (N=671, randomized) comparing PROZAC 20 mg and placebo have shown PROZAC 20 mg 935 daily to be effective in the treatment of elderly patients (≥60 years of age) with Major Depressive Disorder. In these studies, PROZAC 936 produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a 937 total endpoint HAM-D score of ≤8. PROZAC was well tolerated and the rate of treatment discontinuations due to adverse reactions 938 did not differ between PROZAC (12%) and placebo (9%). 939 A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of 940 the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 941 12-week open-treatment phase on PROZAC 20 mg/day. These patients (N=298) were randomized to continuation on double-blind 942 PROZAC 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 943 sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was 944 observed for patients taking PROZAC compared with those on placebo. 945 Pediatric (children and adolescents) — The efficacy of PROZAC 20 mg/day in children and adolescents (N=315 randomized; 946 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) was studied in two 8- to 9-week placebo-controlled clinical trials in 947 depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of Major Depressive 948 Disorder. 949 In both studies independently, PROZAC produced a statistically significantly greater mean change on the Childhood 950 Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. 951 Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. 952 Weekly dosing for Maintenance/Continuation Treatment 953 A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for Major Depressive Disorder who 954 had responded (defined as having a modified HAMD-17 score of ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for 955 Major Depressive Disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with PROZAC 20 mg once daily. 956 These patients were randomized to double-blind, once-weekly continuation treatment with PROZAC Weekly, PROZAC 20 mg once 957 daily, or placebo. PROZAC Weekly once weekly and PROZAC 20 mg once daily demonstrated superior efficacy (having a 958 significantly longer time to relapse of depressive symptoms) compared with placebo for a period of 25 weeks. However, the 959 equivalence of these 2 treatments during continuation therapy has not been established. 960 14.2 Obsessive Compulsive Disorder 961 Adult — The effectiveness of PROZAC for the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in 962 two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed PROZAC doses of 20, 40, 963 or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe 964 OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 965 22 to 26. In Study 1, patients receiving PROZAC experienced mean reductions of approximately 4 to 6 units on the YBOCS total 966 score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving PROZAC experienced mean reductions of 967 approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no 968 indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with 969 numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group 970 on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: 971 972 Table 6 Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies PROZAC Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% 973 974 Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age 975 or sex. 976 Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children 977 ages 7 to <13, 28 adolescents ages 13 to <18) with OCD (DSM-IV), patients received PROZAC 10 mg/day for 2 weeks, followed by 978 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. 979 PROZAC produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the 980 Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). 981 Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. 982 14.3 Bulimia Nervosa 983 The effectiveness of PROZAC for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, 984 parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 985 60 mg/day of PROZAC or placebo in the morning. Patients in the 16-week study received a fixed PROZAC dose of 60 mg/day (once 986 a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies 987 ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, PROZAC 60 mg, but not 20 mg, was statistically 988 significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically 989 significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The 990 PROZAC-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton 991 Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between PROZAC 60 mg and 992 placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for 993 binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 994 reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging 995 as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. 996 In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during 997 a single-blind, 8-week acute treatment phase with PROZAC 60 mg/day, were randomized to continuation of PROZAC 60 mg/day or 998 placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least 999 a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent 000 return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued 001 PROZAC 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving 002 placebo. 003 14.4 Panic Disorder 004 The effectiveness of PROZAC in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, 005 placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without 006 agoraphobia. 007 Study 1 (N=180 randomized) was a 12-week flexible-dose study. PROZAC was initiated at 10 mg/day for the first week, after 008 which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically 009 significantly greater percentage of PROZAC-treated patients were free from panic attacks at endpoint than placebo-treated patients, 010 42% versus 28%, respectively. 011 Study 2 (N=214 randomized) was a 12-week flexible-dose study. PROZAC was initiated at 10 mg/day for the first week, after 012 which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly 013 greater percentage of PROZAC-treated patients were free from panic attacks at endpoint than placebo-treated patients, 014 62% versus 44%, respectively. 015 16 HOW SUPPLIED/STORAGE AND HANDLING 016 16.1 How Supplied 017 The following products are manufactured by Eli Lilly and Company for Dista Products Company: 018 Pulvule are available in 10mg, 20mg and 40mg capsule strengths and packages as follows: 019 Pulvule Strength 10 mg1 20 mg1 40 mg1 Pulvule No.2 PU3104 PU3105 PU3107 Cap Color Opaque green Opaque green Opaque green Body Color Opaque green Opaque yellow Opaque orange Identification DISTA 3104 Prozac 10 mg DISTA 3105 Prozac 20 mg DISTA 3107 Prozac 40 mg NDC Codes: Bottles of 30 0777-3105-30 0777-3107-30 Bottles 100 0777-3104-02 0777-3105-02 Bottles of 2000 0777-3105-07 020 021 The following is manufactured by OSG Norwich Pharmaceuticals, Inc., North Norwich, NY, 13814, for Dista Products 022 Company: 023 Liquid, Oral Solution is available in: 024 20 mg1 per 5 mL with mint flavor: 025 NDC 0777-5120-58 (MS-51203) – Bottles of 120 mL 026 027 The following product is manufactured and distributed by Eli Lilly and Company: 028 PROZAC® Weekly™ Capsules are available in: 029 The 90 mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of 030 the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. 031 NDC 0002-3004-75 (PU3004) – Blister package of 4 032 ______________________ 033 1 Fluoxetine base equivalent. 034 2 Protect from light. 035 3 Dispense in a tight, light-resistant container. 036 037 16.2 Storage and Handling 038 Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 039 17 PATIENT COUNSELING INFORMATION 040 See the FDA-approved Medication Guide. 041 Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking PROZAC as 042 monotherapy or in combination with olanzapine. When using PROZAC and olanzapine in combination, also refer to the Patient 043 Counseling Information section of the package insert for Symbyax. 044 17.1 General Information 045 Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with PROZAC and to 046 reread it each time the prescription is renewed. 047 Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with 048 treatment with PROZAC and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, 049 and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the 050 opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. 051 Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking 052 PROZAC. 053 When using PROZAC and olanzapine in combination, also refer to the Medication Guide for Symbyax. 054 17.2 Clinical Worsening and Suicide Risk 055 Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic 056 attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other 057 unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and 058 when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such 059 symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health 060 professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as 061 these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and 062 possibly changes in the medication [see Box Warning and Warnings and Precautions (5.1)]. 063 17.3 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions 064 Patients should be cautioned about the risk of serotonin syndrome or NMS-like reactions with the concomitant use of 065 PROZAC and triptans, tramadol, or other serotonergic agents [see Warnings and Precautions (5.2) and Drug Interactions (7.3)]. 066 Patients should be advised of the signs and symptoms associated with serotonin syndrome or NMS-like reactions that may 067 include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, 068 hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, 069 vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, in which the 070 symptoms may include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental 071 status changes. Patients should be cautioned to seek medical care immediately if they experience these symptoms. 072 17.4 Allergic Reactions and Rash 073 Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions (5.3)]. 074 Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, 075 eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these 076 symptoms. 077 17.5 Abnormal Bleeding 078 Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect 079 coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated 080 with an increased risk of bleeding [see Warnings and Precautions (5.7) and Drug Interactions (7.6)]. Patients should be advised to 081 call their doctor if they experience any increased or unusual bruising or bleeding while taking PROZAC. 082 17.6 Hyponatremia 083 Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including 084 PROZAC. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, 085 weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, 086 syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions (5.8)]. 087 17.7 Potential for Cognitive and Motor Impairment 088 PROZAC may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating 089 hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions (5.11)]. 090 17.8 Use of Concomitant Medications 091 Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including 092 Symbyax, Sarafem, or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their 093 physicians if they plan to discontinue any medications they are taking while on PROZAC. 094 17.9 Discontinuation of Treatment 095 Patients should be advised to take PROZAC exactly as prescribed, and to continue taking PROZAC as prescribed even after 096 their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking PROZAC without This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 097 consulting their physician [see Warnings and Precautions (5.13)]. Patients should be advised to consult with their healthcare provider 098 if their symptoms do not improve with PROZAC. 099 17.10 Use in Specific Populations 100 Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant 101 during therapy. Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in 102 Specific Populations (8.1)]. 103 Nursing Mothers — Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy. 104 Because PROZAC is excreted in human milk, nursing while taking PROZAC is not recommended [see Use in Specific Populations 105 (8.3)]. 106 Pediatric Use — PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings 107 and Precautions (5.1)]. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and 108 maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving 109 fluoxetine. Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 18 years of age have not been 110 established. 111 [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)]. 112 113 114 115 116 117 118 Eli Lilly and Company 119 Indianapolis, IN 46285, USA 120 121 1.0 C NL 53XX DPP PRINTED IN USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 0.01 NL 7100 AMP Medication Guide PROZAC® (PRO-zac) (fluoxetine hydrochloride) Pulvule®, Oral Solution, WeeklyTM Capsule Read the Medication Guide that comes with PROZAC before you start 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 medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about PROZAC. What is the most important information I should know about PROZAC? Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions: 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 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) • or 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 • 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. What is PROZAC? PROZAC is a prescription medicine used: • for short and long-term treatment of depression in adults and children over the age of 8. • for short and long-term treatment of Obsessive Compulsive Disorder (OCD) in adults and children over the age of 7. • for short and long-term treatment of Bulimia Nervosa in adults. • for short-term treatment of Panic Disorder, with or without agoraphobia, in adults. • with the medicine olanzapine (Zyprexa), for the short-term treatment of episodes of depression that happen with Bipolar I Disorder. • with the medicine olanzapine (Zyprexa), for the short-term treatment of episodes of depression that do not respond to 2 other medicines, also called treatment resistant depression. It is not known if PROZAC and olanzapine (Zyprexa) taken together is safe and works in children under 18 years of age. The symptoms of depression (Major Depressive Disorder, Bipolar I Disorder and Treatment Resistant Depression) include decreased mood, decreased interest, increased guilty feelings, decreased energy, decreased concentration, changes in appetite, and suicidal thoughts or behavior. With treatment, some of your symptoms of depression may improve. OCD is an anxiety disorder and is characterized by recurrent, unwanted thoughts (obsessions) and/or repetitive behaviors (compulsions). With treatment, some of your symptoms of OCD may improve. Panic Disorder is an anxiety disorder that includes panic attacks, which are sudden feelings of terror for no reason. You may also have physical symptoms, such as; fast heartbeat, chest pain, breathing difficulty, dizziness. With treatment, some of your symptoms of Panic Disorder may improve. Bulimia Nervosa, involves periods of overeating followed by purging (e.g. vomiting, excessive laxative use). With treatment, some of your symptoms of Bulimia Nervosa may improve. If you do not think you are getting better, call your doctor. Who should not take PROZAC? • Do not take PROZAC if you take a Monoamine Oxidase Inhibitor (MAOI) or if you stopped taking an MAOI in the last 2 weeks. • Do not take an MAOI within 5 weeks of stopping PROZAC. People who take PROZAC close in time to an MAOI can have serious and life-threatening side effects, with symptoms including: • high fever • continued muscle spasms that you can not control • rigid muscles • changes in heart rate and blood pressure that happen fast • confusion • unconsciousness Ask your doctor or pharmacist if you are not sure if your medicine is an MAOI. • Do not take PROZAC if you take Mellaril® (thioridazine). Do not take Mellaril within 5 weeks of stopping PROZAC. Mellaril can cause serious heart rhythm problems and you could die suddenly. • Do not take PROZAC if you take the antipsychotic medicine pimozide (Orap®). What should I tell my doctor before taking PROZAC? PROZAC may not be right for you. Before starting PROZAC, tell your doctor about all your medical conditions, including if you have or had any of the following: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 • seizures (convulsions) • bipolar disorder (mania) • are pregnant or plan to become pregnant. It is not known if PROZAC will harm your unborn baby. • are breast-feeding or plan to breast-feed. PROZAC can pass into your breast milk and may harm your baby. You should not breast-feed while taking PROZAC. Talk to your doctor about the best way to feed your baby if you take PROZAC. Tell your doctor about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. PROZAC and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take PROZAC with your other medicines. Do not start or stop any medicine while taking PROZAC without talking to your doctor first. If you take PROZAC, you should not take any other medicines that contain fluoxetine hydrochloride: • Symbyax • Sarafem • Prozac Weekly You could take too much medicine (overdose). How should I take PROZAC? • Take PROZAC exactly as prescribed. Your doctor may need to change (adjust) the dose of PROZAC until it is right for you. • If you miss a dose of PROZAC, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of PROZAC at the same time. • To prevent serious side effects, do not stop taking PROZAC suddenly. If you need to stop taking PROZAC, your doctor can tell you how to safely stop taking it. • If you take too much PROZAC, call your doctor or poison control center right away, or get emergency treatment. • PROZAC can be taken with or without food. • PROZAC is usually taken once a day or once weekly, depending on how your doctor prescribes your medicine. • If you do not think you are getting better or have any concerns about your condition while taking PROZAC, call your doctor. What should I avoid while taking PROZAC? • PROZAC can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how PROZAC affects you. What are the possible side effects of PROZAC? PROZAC may be associated with the following serious risks: • Serotonin Syndrome: This is a condition that can be life threatening. Call your doctor right away if you become severely ill and have some or all of these symptoms: • agitation • hallucinations • problems with coordination • racing heart beat • over-active reflexes • fever • nausea, vomiting, and diarrhea • Severe allergic reactions: Tell your doctor right away if you get red itchy welts (hives) or, a rash alone or with fever and joint pain, while taking PROZAC. Call your doctor right away if you become severely ill and have some or all of these symptoms: • swelling of your face, eyes, or mouth • trouble breathing This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 • Abnormal bleeding: Tell your doctor if you notice any increased or unusual bruising or bleeding while taking PROZAC, especially if you take one of these medicines: • the blood thinner warfarin (Coumadin, Jantoven) • a non-steroidal anti-inflammatory drug (NSAID) • aspirin • Mania: You may have a high mood, become extremely irritable, have too much energy, feel pressure to keep talking, or have a decreased need for sleep. • Seizures • Loss of appetite • Low salt (sodium) levels in the blood (hyponatremia): Call your doctor right away if you become severely ill and have some or all of these symptoms: • headache • feel weak • confusion • problems concentrating • memory problems • feel unsteady Common possible side effects of PROZAC include: abnormal dreams, orgasm problems, decreased appetite, anxiety, weakness, diarrhea, dry mouth, indigestion, flu, difficulty maintaining an erection for sexual activity, trouble sleeping, decreased sex drive, feeling sick to your stomach, nervousness, sore throat, rash, watery nasal discharge, sleepiness, sweating, tremor (shakes), hot flashes, and yawn. Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects with PROZAC. For more information, ask your doctor 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 PROZAC? • Store PROZAC at room temperature, between 59°F to 86°F (15°C to 30°C). • Keep PROZAC away from light. • Keep PROZAC bottle closed tightly. Keep PROZAC and all medicines out of the reach of children. General information about PROZAC Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PROZAC for a condition for which it was not prescribed. Do not give PROZAC to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about PROZAC. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about PROZAC that was written for healthcare professionals. For more information about PROZAC call 1-800-Lilly-Rx (1-800-545-5979) or visit www.prozac.com. What are the ingredients in PROZAC? Active ingredients: fluoxetine hydrochloride Inactive ingredients in pulvules: starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- and 20-mg pulvules also contain FD&C Blue No. 1, and the 40-mg pulvules also contains FD&C Blue No. 1 and FD&C Yellow No. 6. Inactive ingredients in oral solution: 0.23% alcohol, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. Inactive ingredients in PROZAC Weekly™ capsules: D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium oxide, triethyl citrate, and other inactive ingredients. This Medication Guide has been approved by the U.S. Food and Drug Administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Medication Guide revised Month DD, YYYY Eli Lilly and Company Indianapolis, IN 46285, USA www.prozac.com Copyright © 2008, 2009 Eli Lilly and Company. All rights reserved. 0.01 NL 7100 AMP PRINTED IN USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:04.455588	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018936s075s077lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 77}
11,374	1 1 2 3 4 5 PV 5324 DPP PROZAC® FLUOXETINE CAPSULES, USP FLUOXETINE ORAL SOLUTION, USP FLUOXETINE DELAYED-RELEASE CAPSULES, USP WARNING 6 Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to 7 placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young 8 adults in short-term studies of major depressive disorder (MDD) and other psychiatric 9 disorders. Anyone considering the use of Prozac or any other antidepressant in a child, 10 adolescent, or young adult must balance this risk with the clinical need. Short-term studies 11 did not show an increase in the risk of suicidality with antidepressants compared to 12 placebo in adults beyond age 24; there was a reduction in risk with antidepressants 13 compared to placebo in adults aged 65 and older. Depression and certain other psychiatric 14 disorders are themselves associated with increases in the risk of suicide. Patients of all ages 15 who are started on antidepressant therapy should be monitored appropriately and 16 observed closely for clinical worsening, suicidality, or unusual changes in behavior. 17 Families and caregivers should be advised of the need for close observation and 18 communication with the prescriber. Prozac is approved for use in pediatric patients with 19 MDD and obsessive compulsive disorder (OCD). (See WARNINGS, Clinical Worsening 20 and Suicide Risk, PRECAUTIONS, Information for Patients, and PRECAUTIONS, 21 Pediatric Use.) 22 23 24 25 26 27 28 DESCRIPTION Prozac® (fluoxetine capsules, USP and fluoxetine oral solution, USP) is a psychotropic drug for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α- trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: 29 30 31 32 33 34 35 36 37 38 39 Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- and 20-mg Pulvules also contain FD&C Blue No. 1, and the 40-mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 μmol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Prozac Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 μmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 CLINICAL PHARMACOLOGY Pharmacodynamics The antidepressant, antiobsessive compulsive, and antibulimic actions of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. Absorption, Distribution, Metabolism, and Excretion Systemic bioavailability — In man, following a single oral 40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The Pulvule, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS). Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical issues related to metabolism/elimination — The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine’s clinical use. Variability in metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as 83 84 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. 85 86 87 88 89 90 91 92 93 94 95 96 97 98 Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see Drug Interactions under PRECAUTIONS). Accumulation and slow elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of Prozac. Weekly dosing — Administration of Prozac Weekly once weekly results in increased fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of clinical response. Peak concentrations from once-weekly doses of Prozac Weekly capsules of fluoxetine are in the range of the average concentration for 20-mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20-mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly dosing are in relative proportion to the total dose administered. Average steady-state fluoxetine concentrations are approximately 50% lower following the once-weekly regimen compared with the once-daily regimen. Cmax for fluoxetine following the 90-mg dose was approximately 1.7-fold higher than the Cmax value for the established 20-mg once-daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90-mg once-weekly dose and the last 20-mg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better to separate the first 90-mg weekly dose and the last 20-mg once-daily dose by 1 week (see 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 DOSAGE AND ADMINISTRATION). Liver disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Renal disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (see Use in Patients with Concomitant Illness under PRECAUTIONS and DOSAGE AND ADMINISTRATION). Age Geriatric pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse events was observed in those elderly patients. 153 154 155 156 157 158 159 160 161 162 Pediatric pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with major depressive disorder or obsessive compulsive disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with major depressive disorder. 163 164 165 166 167 168 169 170 171 172 173 174 175 176 Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. 177 178 179 180 181 CLINICAL TRIALS Major Depressive Disorder Daily Dosing Adult — The efficacy of Prozac for the treatment of patients with major depressive disorder (≥18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Prozac was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 Two 6-week controlled studies (N=671, randomized) comparing Prozac 20 mg and placebo have shown Prozac 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with major depressive disorder. In these studies, Prozac produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. Prozac was well tolerated and the rate of treatment discontinuations due to adverse events did not differ between Prozac (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on Prozac 20 mg/day. These patients (N=298) were randomized to continuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of major depressive disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking Prozac compared with those on placebo. Pediatric (children and adolescents) — The efficacy of Prozac 20 mg/day for the treatment of major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) has been studied in two 8- to 9-week placebo-controlled clinical trials. 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 In both studies independently, Prozac produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Weekly dosing for maintenance/continuation treatment A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded (defined as having a modified HAMD-17 score of ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for major depressive disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with Prozac 20 mg once daily. These patients were randomized to double-blind, once-weekly continuation treatment with Prozac Weekly, Prozac 20 mg once daily, or placebo. Prozac Weekly once weekly and Prozac 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of depressive symptoms) compared with placebo for a period of 25 weeks. However, the equivalence of these 2 treatments during continuation therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Obsessive Compulsive Disorder 220 Adult — The effectiveness of Prozac for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Prozac Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% 238 239 240 Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD, patients received Prozac 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Prozac produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. Bulimia Nervosa The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of Prozac or placebo in the morning. Patients in the 16-week study received a fixed Prozac dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, Prozac 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 and persisted throughout each study. The Prozac-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between Prozac 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with Prozac 60 mg/day, were randomized to continuation of Prozac 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued Prozac 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. Panic Disorder The effectiveness of Prozac in the treatment of panic disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia. Study 1 (N=180 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N=214 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively. INDICATIONS AND USAGE Major Depressive Disorder Prozac is indicated for the treatment of major depressive disorder. Adult — The efficacy of Prozac was established in 5- and 6-week trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of major depressive disorder (see 295 296 297 298 299 300 301 302 303 304 CLINICAL TRIALS). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The effects of Prozac in hospitalized depressed patients have not been adequately studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 The efficacy of Prozac 20 mg once daily in maintaining a response in major depressive disorder for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) was demonstrated in a placebo-controlled trial. 305 306 307 308 309 310 311 312 313 The efficacy of Prozac Weekly once weekly in maintaining a response in major depressive disorder has been demonstrated in a placebo-controlled trial for up to 25 weeks following open-label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38 weeks. However, it is unknown whether or not Prozac Weekly given on a once-weekly basis provides the same level of protection from relapse as that provided by Prozac 20 mg daily (see CLINICAL TRIALS). Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see 314 315 316 317 318 319 320 CLINICAL TRIALS). The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should be reevaluated periodically. Obsessive Compulsive Disorder Adult — Prozac is indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. 321 322 323 324 325 326 327 328 329 330 331 332 333 334 The efficacy of Prozac was established in 13-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-III-R category of OCD (see CLINICAL TRIALS). OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. The effectiveness of Prozac in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in DSM-IV (see 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 CLINICAL TRIALS). Bulimia Nervosa Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa. The efficacy of Prozac was established in 8- to 16-week trials for adult outpatients with moderate to severe bulimia nervosa, i.e., at least 3 bulimic episodes per week for 6 months (see CLINICAL TRIALS). The efficacy of Prozac 60 mg/day in maintaining a response, in patients with bulimia who responded during an 8-week acute treatment phase while taking Prozac 60 mg/day and were then observed for relapse during a period of up to 52 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (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 9 Panic Disorder 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 Prozac is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks, and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of Prozac was established in two 12-week clinical trials in patients whose diagnoses corresponded to the DSM-IV category of panic disorder (see CLINICAL TRIALS). Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 or more of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear of dying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes. The effectiveness of Prozac in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Prozac is contraindicated in patients known to be hypersensitive to it. Monoamine oxidase inhibitors — There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Prozac should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY)] should be allowed after stopping Prozac before starting an MAOI. Pimozide — Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS). Thioridazine — Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after Prozac has been discontinued (see WARNINGS). 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) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 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. 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 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 versus 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 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 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. 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Prozac, for a description of the risks of discontinuation of Prozac). 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 Prozac should be written for the smallest quantity of capsules, or liquid consistent with good patient management, in order to reduce the risk of overdose. It should be noted that Prozac is approved in the pediatric population only for major depressive disorder and obsessive compulsive disorder. 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 Prozac is not approved for use in treating bipolar depression. Rash and Possibly Allergic Events — In US fluoxetine clinical trials as of May 8, 1995, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely. In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of Prozac, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac should be discontinued. Serotonin Syndrome — The development of a potentially life-threatening serotonin syndrome may occur with SNRIs and SSRIs, including Prozac treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Prozac with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and Drug Interactions under PRECAUTIONS). If concomitant treatment Prozac with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Drug Interactions under PRECAUTIONS). The concomitant use of Prozac with serotonin precursors (such as tryptophan) is not recommended (see Drug Interactions under PRECAUTIONS). Potential Interaction with Thioridazine — In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS). Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS). PRECAUTIONS General Abnormal Bleeding — Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 be cautioned regarding the risk of bleeding associated with the concomitant use of Prozac with NSAIDs, aspirin, or other drugs that affect coagulation. 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 Anxiety and Insomnia — In US placebo-controlled clinical trials for major depressive disorder, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Prozac and in 7% of patients treated with placebo. In US placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with Prozac 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with Prozac 60 mg and in 9% and 5% of patients treated with placebo. Among the most common adverse events associated with discontinuation (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in major depressive disorder) (see Table 4). Altered Appetite and Weight — Significant weight loss, especially in underweight depressed or bulimic patients may be an undesirable result of treatment with Prozac. In US placebo-controlled clinical trials for major depressive disorder, 11% of patients treated with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Prozac because of anorexia or weight loss (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Prozac because of anorexia (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Prozac 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy. Activation of Mania/Hypomania — In US placebo-controlled clinical trials for major depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Prozac and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of major depressive disorder (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Prozac and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see also Pediatric Use under PRECAUTIONS). Hyponatremia — Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when Prozac was discontinued. Although these cases were complex with varying possible etiologies, some were possibly due to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted. In two 6-week controlled studies in patients ≥60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration was 129 mmol/L. The observed decreases were not clinically significant. 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 Seizures — In US placebo-controlled clinical trials for major depressive disorder, convulsions (or events described as possibly having been seizures) were reported in 0.1% of patients treated with Prozac and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of major depressive disorder. Prozac should be introduced with care in patients with a history of seizures. The Long Elimination Half-Lives of Fluoxetine and its Metabolites — Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Use in Patients with Concomitant Illness — Clinical experience with Prozac in patients with concomitant systemic illness is limited. Caution is advisable in using Prozac in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received Prozac in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose should be used in patients with cirrhosis. Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma (see Renal disease under CLINICAL PHARMACOLOGY). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE AND ADMINISTRATION). In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred during therapy with Prozac, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with Prozac is instituted or discontinued. Interference with Cognitive and Motor Performance — Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Discontinuation of Treatment with Prozac — During marketing of Prozac and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Prozac. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 DOSAGE AND ADMINISTRATION). 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 Prozac 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 Prozac. 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 Prozac. 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. Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Prozac and triptans, tramadol or other serotonergic agents. Because Prozac may impair judgment, thinking, or motor skills, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected. Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs, or alcohol. Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Patients should be advised to notify their physician if they are breast-feeding an infant. 661 662 663 664 665 666 667 668 Patients should be advised to notify their physician if they develop a rash or hives. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 CONTRAINDICATIONS and WARNINGS). Drugs metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. 685 686 687 688 689 690 691 CNS active drugs — The risk of using Prozac in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Prozac and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see 692 693 694 695 696 697 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. 698 699 700 Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT 701 702 703 704 705 706 c prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 concurrent use of pimozide and Prozac. Concomitant use of Prozac and pimozide is contraindicated (see 707 708 709 CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS and WARNINGS. Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients (see 710 711 712 713 714 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. 715 716 717 718 Tryptophan — Five patients receiving Prozac in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. 719 720 Monoamine oxidase inhibitors — See CONTRAINDICATIONS. 721 Other drugs effective in the treatment of major depressive disorder — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see 722 723 724 725 726 727 728 Accumulation and slow elimination under CLINICAL PHARMACOLOGY, and Drugs metabolized by CYP2D6 under Drug Interactions). Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including Prozac, and the potential for serotonin syndrome, caution is advised when Prozac is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see 729 730 731 732 733 734 Serotonin Syndrome under WARNINGS). The concomitant use of Prozac with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Prozac with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see 735 736 737 738 Serotonin Syndrome under WARNINGS). Potential effects of coadministration of drugs tightly bound to plasma proteins — Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs (see 739 740 741 742 743 744 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs that interfere with hemostasis (NSAIDs, aspirin, warfarin, etc.) — Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluoxetine. 745 746 747 748 749 750 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Warfarin — Altered anticoagulant effects, including increased bleeding, have been reported when fluoxetine is coadministered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped. 751 752 753 Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. 754 755 756 757 758 759 760 Carcinogenesis, Mutagenesis, Impairment of Fertility There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) was not observed. Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m 761 762 763 764 2 basis], produced no evidence of carcinogenicity. Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. 765 766 767 768 Impairment of fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 2 basis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use). Pregnancy Pregnancy Category C — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects — Neonates exposed to Prozac and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Monoamine oxidase inhibitors under CONTRAINDICATIONS). Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 When treating a pregnant woman with Prozac during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. Labor and Delivery The effect of Prozac on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. Pediatric Use The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 (see CLINICAL TRIALS). The efficacy of Prozac for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 (see CLINICAL TRIALS). The safety and effectiveness in pediatric patients <8 years of age in major depressive disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major depressive disorder or OCD (see Pharmacokinetics under CLINICAL PHARMACOLOGY). The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse event profile observed in the 19-week major depressive disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS). Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. (See WARNINGS, Clinical Worsening and Suicide Risk.) Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis. In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain. Prozac is approved for use in pediatric patients with MDD and OCD (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Prozac in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use US fluoxetine clinical trials as of May 8, 1995 (10,782 patients) included 687 patients ≥65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric patients has been established (see CLINICAL TRIALS). For pharmacokinetic information in geriatric patients, see Age under CLINICAL PHARMACOLOGY. No overall differences in safety or 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. As with other SSRIs, fluoxetine has been associated with cases of clinically significant hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS). ADVERSE REACTIONS Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered Prozac in panic clinical trials. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled 926 clinical trials (excluding data from extensions of trials) — Table 2 enumerates the most common treatment-emergent adverse events associated with the use of Prozac (incidence of at least 5% for Prozac and at least twice that for placebo within at least 1 of the indications) for the treatment of major depressive disorder, OCD, and bulimia in US controlled clinical trials and panic disorder in US plus non-US controlled trials. Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more patients treated with Prozac and with incidence greater than placebo who participated in US major depressive disorder, OCD, and bulimia controlled clinical trials and US 927 928 929 930 931 932 933 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 plus non-US panic disorder controlled clinical trials. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2. 934 935 936 937 938 939 Table 2: Most Common Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Event Prozac (N=1728) Placebo (N=975) Prozac (N=266) Placebo (N=89) Prozac (N=450) Placebo (N=267) Prozac (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence2 2 -- -- -- 7 -- 1 -- Abnormal ejaculation2 -- -- 7 -- 7 -- 2 1 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. 940 941 942 943 944 945 946 2 Denominator used was for males only (N=690 Prozac major depressive disorder; N=410 placebo major depressive disorder; N=116 Prozac OCD; N=43 placebo OCD; N=14 Prozac bulimia; N=1 placebo bulimia; N=162 Prozac panic; N=121 placebo panic). -- Incidence less than 1%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Table 3: Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 947 948 1 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Event2 Prozac (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. 949 950 951 952 953 954 955 956 2 Included are events reported by at least 2% of patients taking Prozac, except the following events, which had an incidence on placebo ≥ Prozac (major depressive disorder, OCD, bulimia, and panic disorder combined): abdominal pain, abnormal dreams, accidental injury, back pain, cough increased, major depressive disorder (includes suicidal thoughts), dysmenorrhea, infection, myalgia, pain, paresthesia, pharyngitis, rhinitis, sinusitis. -- Incidence less than 1%. Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic 957 disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 4 lists the adverse events associated with discontinuation of Prozac treatment (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. 958 959 960 961 962 963 964 965 966 Table 4: Most Common Adverse Events Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) -- -- Rash (1%) -- -- 1 Includes US major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. 967 968 969 Other adverse events in pediatric patients (children and adolescents) — Treatment-emergent adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse events was generally similar to that seen in adult studies, as shown in Tables 2 and 3. However, the following adverse events (excluding those which appear in the body or footnotes of Tables 2 and 3 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. 970 971 972 973 974 975 976 977 978 979 980 981 982 The most common adverse event (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary event associated with discontinuation was collected. Events observed in Prozac Weekly clinical trials — Treatment-emergent adverse events in clinical trials with Prozac Weekly were similar to the adverse events reported by patients in clinical trials with Prozac daily. In a placebo-controlled clinical trial, more patients taking Prozac Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking Prozac 20 mg daily (10% versus 5%, respectively). 983 984 985 986 987 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US major depressive disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Other Events Observed in Clinical Trials Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking fluoxetine in US clinical trials as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 2 or 3 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to Prozac use was considered remote; and (4) events occurring in only 1 patient treated with Prozac and which did not have a substantial probability of being acutely life-threatening. Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients. Body as a Whole — Frequent: chest pain, chills; Infrequent: chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome1, photosensitivity reaction. Cardiovascular System — Frequent: hemorrhage, hypertension, palpitation; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. Digestive System — Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Endocrine System — Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 Hemic and Lymphatic System — Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia. Metabolic and Nutritional — Frequent: weight gain; Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. Musculoskeletal System — Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis. Nervous System — Frequent: agitation, amnesia, confusion, emotional lability, sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder2, psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor. Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor. Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect. Urogenital System — Frequent: urinary frequency; Infrequent: abortion3, albuminuria, amenorrhea3, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation3, fibrocystic breast3, hematuria, leukorrhea3, menorrhagia3, metrorrhagia3, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage3; Rare: breast engorgement, glycosuria, hypomenorrhea3, kidney pain, oliguria, priapism3, uterine hemorrhage3, uterine fibroids enlarged3. 1 Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome. 2 Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. 3 Adjusted for gender. Postintroduction Reports Voluntary reports of adverse events temporally associated with Prozac that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors. 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 DRUG ABUSE AND DEPENDENCE Controlled substance class — Prozac is not a controlled substance. Physical and psychological dependence — Prozac has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope. 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (see Management of Overdose). Management of Overdose Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS). Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 DOSAGE AND ADMINISTRATION 1168 1169 1170 Major Depressive Disorder Initial Treatment Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in major depressive disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. 1171 1172 1173 1174 1175 1176 1177 1178 A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of major depressive disorder, patients were administered fluoxetine doses of 10 to 20 mg/day (see 1179 1180 1181 1182 1183 1184 1185 1186 CLINICAL TRIALS). Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. All patients — As with other drugs effective in the treatment of major depressive disorder, the full effect may be delayed until 4 weeks of treatment or longer. 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Daily Dosing Systematic evaluation of Prozac in adult patients has shown that its efficacy in major depressive disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day (see CLINICAL TRIALS). Weekly Dosing Systematic evaluation of Prozac Weekly in adult patients has shown that its efficacy in major depressive disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment with Prozac 20 mg once daily. However, therapeutic equivalence of Prozac Weekly given on a once-weekly basis with Prozac 20 mg given daily for delaying time to relapse has not been established (see CLINICAL TRIALS). Weekly dosing with Prozac Weekly capsules is recommended to be initiated 7 days after the last daily dose of Prozac 20 mg (see Weekly dosing under CLINICAL PHARMACOLOGY). If satisfactory response is not maintained with Prozac Weekly, consider reestablishing a daily dosing regimen (see CLINICAL TRIALS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 Switching Patients to a Tricyclic Antidepressant (TCA) 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS, Drug Interactions). Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping Prozac before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS). Obsessive Compulsive Disorder Initial Treatment Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo (see 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 CLINICAL TRIALS). In 1 of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once-a-day (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 CLINICAL TRIALS). In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. All patients — As with the use of Prozac in the treatment of major depressive disorder, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment While there are no systematic studies that answer the question of how long to continue Prozac, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of Prozac after 13 weeks has not been documented in controlled trials, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 Bulimia Nervosa Initial Treatment In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo (see CLINICAL TRIALS). Only the 60-mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. As with the use of Prozac in the treatment of major depressive disorder and OCD, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment Systematic evaluation of continuing Prozac 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking Prozac 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment (see CLINICAL TRIALS). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Panic Disorder Initial Treatment In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of panic disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see CLINICAL TRIALS). Treatment should be initiated with a dose of 10 mg/day. After 1 week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with panic disorder. As with the use of Prozac in other indications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 Maintenance/Continuation Treatment 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 While there are no systematic studies that answer the question of how long to continue Prozac, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Prozac and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Prozac during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Prozac in the third trimester. Discontinuation of Treatment with Prozac Symptoms associated with discontinuation of Prozac and other SSRIs and SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. HOW SUPPLIED The following products are manufactured by Eli Lilly and Company for Dista Products Company. Prozac® Pulvules®, USP, are available in: The 10-mg1, Pulvule is opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body: NDC 0777-3104-02 (PU31042) - Bottles of 100 The 20-mg1 Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body: NDC 0777-3105-30 (PU31052) - Bottles of 30 NDC 0777-3105-02 (PU31052) - Bottles of 100 NDC 0777-3105-07 (PU31052) - Bottles of 2000 The 40-mg1 Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body: NDC 0777-3107-30 (PU31072) - Bottles of 30 The following is manufactured by OSG Norwich Pharmaceuticals, Inc., North Norwich, NY, 13814, for Dista Products Company: Liquid, Oral Solution is available in: 20 mg1 per 5 mL with mint flavor: NDC 0777-5120-58 (MS-51203) - Bottles of 120 mL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 The following product is manufactured and distributed by Eli Lilly and Company: Prozac® Weekly™ Capsules are available in: The 90-mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) - Blister package of 4 ______________________ 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1 Fluoxetine base equivalent. 2 Protect from light. 3 Dispense in a tight, light-resistant container. Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). ANIMAL TOXICOLOGY Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. Literature revised June 21, 2007 Eli Lilly and Company Indianapolis, IN 46285, USA www.lilly.com PV 5324 DPP PRINTED IN USA 1341 Medication Guide 1342 Antidepressant Medicines, Depression and other Serious Mental 1343 Illnesses, and Suicidal Thoughts or Actions 1344 1345 1346 1347 1348 1349 1350 Read the Medication Guide that comes with your 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 1351 medicines, depression and other serious mental illnesses, and suicidal thoughts 1352 or actions? 1353 1354 1355 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 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. 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 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 What else do I need to know about antidepressant medicines? 1385 1386 1387 1388 1389 1390 1391 • 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:04.467692	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018936s081s082,020101s037,021235s009lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 82}
11,373	1 1 2 3 4 5 PV 5324 DPP PROZAC® FLUOXETINE CAPSULES, USP FLUOXETINE ORAL SOLUTION, USP FLUOXETINE DELAYED-RELEASE CAPSULES, USP WARNING 6 Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to 7 placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young 8 adults in short-term studies of major depressive disorder (MDD) and other psychiatric 9 disorders. Anyone considering the use of Prozac or any other antidepressant in a child, 10 adolescent, or young adult must balance this risk with the clinical need. Short-term studies 11 did not show an increase in the risk of suicidality with antidepressants compared to 12 placebo in adults beyond age 24; there was a reduction in risk with antidepressants 13 compared to placebo in adults aged 65 and older. Depression and certain other psychiatric 14 disorders are themselves associated with increases in the risk of suicide. Patients of all ages 15 who are started on antidepressant therapy should be monitored appropriately and 16 observed closely for clinical worsening, suicidality, or unusual changes in behavior. 17 Families and caregivers should be advised of the need for close observation and 18 communication with the prescriber. Prozac is approved for use in pediatric patients with 19 MDD and obsessive compulsive disorder (OCD). (See WARNINGS, Clinical Worsening 20 and Suicide Risk, PRECAUTIONS, Information for Patients, and PRECAUTIONS, 21 Pediatric Use.) 22 23 24 25 26 27 28 DESCRIPTION Prozac® (fluoxetine capsules, USP and fluoxetine oral solution, USP) is a psychotropic drug for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α- trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: 29 30 31 32 33 34 35 36 37 38 39 Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- and 20-mg Pulvules also contain FD&C Blue No. 1, and the 40-mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 μmol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Prozac Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 μmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 CLINICAL PHARMACOLOGY Pharmacodynamics The antidepressant, antiobsessive compulsive, and antibulimic actions of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. Absorption, Distribution, Metabolism, and Excretion Systemic bioavailability — In man, following a single oral 40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The Pulvule, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS). Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical issues related to metabolism/elimination — The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine’s clinical use. Variability in metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as 83 84 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. 85 86 87 88 89 90 91 92 93 94 95 96 97 98 Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see Drug Interactions under PRECAUTIONS). Accumulation and slow elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of Prozac. Weekly dosing — Administration of Prozac Weekly once weekly results in increased fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of clinical response. Peak concentrations from once-weekly doses of Prozac Weekly capsules of fluoxetine are in the range of the average concentration for 20-mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20-mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly dosing are in relative proportion to the total dose administered. Average steady-state fluoxetine concentrations are approximately 50% lower following the once-weekly regimen compared with the once-daily regimen. Cmax for fluoxetine following the 90-mg dose was approximately 1.7-fold higher than the Cmax value for the established 20-mg once-daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90-mg once-weekly dose and the last 20-mg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better to separate the first 90-mg weekly dose and the last 20-mg once-daily dose by 1 week (see 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 DOSAGE AND ADMINISTRATION). Liver disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Renal disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (see Use in Patients with Concomitant Illness under PRECAUTIONS and DOSAGE AND ADMINISTRATION). Age Geriatric pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse events was observed in those elderly patients. 153 154 155 156 157 158 159 160 161 162 Pediatric pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with major depressive disorder or obsessive compulsive disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with major depressive disorder. 163 164 165 166 167 168 169 170 171 172 173 174 175 176 Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. 177 178 179 180 181 CLINICAL TRIALS Major Depressive Disorder Daily Dosing Adult — The efficacy of Prozac for the treatment of patients with major depressive disorder (≥18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Prozac was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 Two 6-week controlled studies (N=671, randomized) comparing Prozac 20 mg and placebo have shown Prozac 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with major depressive disorder. In these studies, Prozac produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. Prozac was well tolerated and the rate of treatment discontinuations due to adverse events did not differ between Prozac (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on Prozac 20 mg/day. These patients (N=298) were randomized to continuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of major depressive disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking Prozac compared with those on placebo. Pediatric (children and adolescents) — The efficacy of Prozac 20 mg/day for the treatment of major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) has been studied in two 8- to 9-week placebo-controlled clinical trials. 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 In both studies independently, Prozac produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Weekly dosing for maintenance/continuation treatment A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded (defined as having a modified HAMD-17 score of ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for major depressive disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with Prozac 20 mg once daily. These patients were randomized to double-blind, once-weekly continuation treatment with Prozac Weekly, Prozac 20 mg once daily, or placebo. Prozac Weekly once weekly and Prozac 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of depressive symptoms) compared with placebo for a period of 25 weeks. However, the equivalence of these 2 treatments during continuation therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Obsessive Compulsive Disorder 220 Adult — The effectiveness of Prozac for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Prozac Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% 238 239 240 Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD, patients received Prozac 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Prozac produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. Bulimia Nervosa The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of Prozac or placebo in the morning. Patients in the 16-week study received a fixed Prozac dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, Prozac 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 and persisted throughout each study. The Prozac-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between Prozac 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with Prozac 60 mg/day, were randomized to continuation of Prozac 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued Prozac 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. Panic Disorder The effectiveness of Prozac in the treatment of panic disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia. Study 1 (N=180 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N=214 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively. INDICATIONS AND USAGE Major Depressive Disorder Prozac is indicated for the treatment of major depressive disorder. Adult — The efficacy of Prozac was established in 5- and 6-week trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of major depressive disorder (see 295 296 297 298 299 300 301 302 303 304 CLINICAL TRIALS). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The effects of Prozac in hospitalized depressed patients have not been adequately studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 The efficacy of Prozac 20 mg once daily in maintaining a response in major depressive disorder for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) was demonstrated in a placebo-controlled trial. 305 306 307 308 309 310 311 312 313 The efficacy of Prozac Weekly once weekly in maintaining a response in major depressive disorder has been demonstrated in a placebo-controlled trial for up to 25 weeks following open-label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38 weeks. However, it is unknown whether or not Prozac Weekly given on a once-weekly basis provides the same level of protection from relapse as that provided by Prozac 20 mg daily (see CLINICAL TRIALS). Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see 314 315 316 317 318 319 320 CLINICAL TRIALS). The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should be reevaluated periodically. Obsessive Compulsive Disorder Adult — Prozac is indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. 321 322 323 324 325 326 327 328 329 330 331 332 333 334 The efficacy of Prozac was established in 13-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-III-R category of OCD (see CLINICAL TRIALS). OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. The effectiveness of Prozac in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in DSM-IV (see 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 CLINICAL TRIALS). Bulimia Nervosa Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa. The efficacy of Prozac was established in 8- to 16-week trials for adult outpatients with moderate to severe bulimia nervosa, i.e., at least 3 bulimic episodes per week for 6 months (see CLINICAL TRIALS). The efficacy of Prozac 60 mg/day in maintaining a response, in patients with bulimia who responded during an 8-week acute treatment phase while taking Prozac 60 mg/day and were then observed for relapse during a period of up to 52 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (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 9 Panic Disorder 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 Prozac is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks, and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of Prozac was established in two 12-week clinical trials in patients whose diagnoses corresponded to the DSM-IV category of panic disorder (see CLINICAL TRIALS). Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 or more of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear of dying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes. The effectiveness of Prozac in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Prozac is contraindicated in patients known to be hypersensitive to it. Monoamine oxidase inhibitors — There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Prozac should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY)] should be allowed after stopping Prozac before starting an MAOI. Pimozide — Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS). Thioridazine — Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after Prozac has been discontinued (see WARNINGS). 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) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 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. 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 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 versus 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 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 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. 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Prozac, for a description of the risks of discontinuation of Prozac). 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 Prozac should be written for the smallest quantity of capsules, or liquid consistent with good patient management, in order to reduce the risk of overdose. It should be noted that Prozac is approved in the pediatric population only for major depressive disorder and obsessive compulsive disorder. 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 Prozac is not approved for use in treating bipolar depression. Rash and Possibly Allergic Events — In US fluoxetine clinical trials as of May 8, 1995, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely. In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of Prozac, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac should be discontinued. Serotonin Syndrome — The development of a potentially life-threatening serotonin syndrome may occur with SNRIs and SSRIs, including Prozac treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Prozac with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and Drug Interactions under PRECAUTIONS). If concomitant treatment Prozac with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Drug Interactions under PRECAUTIONS). The concomitant use of Prozac with serotonin precursors (such as tryptophan) is not recommended (see Drug Interactions under PRECAUTIONS). Potential Interaction with Thioridazine — In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS). Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS). PRECAUTIONS General Abnormal Bleeding — Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 be cautioned regarding the risk of bleeding associated with the concomitant use of Prozac with NSAIDs, aspirin, or other drugs that affect coagulation. 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 Anxiety and Insomnia — In US placebo-controlled clinical trials for major depressive disorder, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Prozac and in 7% of patients treated with placebo. In US placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with Prozac 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with Prozac 60 mg and in 9% and 5% of patients treated with placebo. Among the most common adverse events associated with discontinuation (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in major depressive disorder) (see Table 4). Altered Appetite and Weight — Significant weight loss, especially in underweight depressed or bulimic patients may be an undesirable result of treatment with Prozac. In US placebo-controlled clinical trials for major depressive disorder, 11% of patients treated with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Prozac because of anorexia or weight loss (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Prozac because of anorexia (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Prozac 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy. Activation of Mania/Hypomania — In US placebo-controlled clinical trials for major depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Prozac and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of major depressive disorder (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Prozac and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see also Pediatric Use under PRECAUTIONS). Hyponatremia — Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when Prozac was discontinued. Although these cases were complex with varying possible etiologies, some were possibly due to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted. In two 6-week controlled studies in patients ≥60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration was 129 mmol/L. The observed decreases were not clinically significant. 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 Seizures — In US placebo-controlled clinical trials for major depressive disorder, convulsions (or events described as possibly having been seizures) were reported in 0.1% of patients treated with Prozac and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of major depressive disorder. Prozac should be introduced with care in patients with a history of seizures. The Long Elimination Half-Lives of Fluoxetine and its Metabolites — Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Use in Patients with Concomitant Illness — Clinical experience with Prozac in patients with concomitant systemic illness is limited. Caution is advisable in using Prozac in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received Prozac in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose should be used in patients with cirrhosis. Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma (see Renal disease under CLINICAL PHARMACOLOGY). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE AND ADMINISTRATION). In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred during therapy with Prozac, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with Prozac is instituted or discontinued. Interference with Cognitive and Motor Performance — Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Discontinuation of Treatment with Prozac — During marketing of Prozac and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Prozac. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 DOSAGE AND ADMINISTRATION). 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 Prozac 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 Prozac. 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 Prozac. 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. Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Prozac and triptans, tramadol or other serotonergic agents. Because Prozac may impair judgment, thinking, or motor skills, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected. Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs, or alcohol. Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Patients should be advised to notify their physician if they are breast-feeding an infant. 661 662 663 664 665 666 667 668 Patients should be advised to notify their physician if they develop a rash or hives. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 CONTRAINDICATIONS and WARNINGS). Drugs metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. 685 686 687 688 689 690 691 CNS active drugs — The risk of using Prozac in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Prozac and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see 692 693 694 695 696 697 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. 698 699 700 Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT 701 702 703 704 705 706 c prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 concurrent use of pimozide and Prozac. Concomitant use of Prozac and pimozide is contraindicated (see 707 708 709 CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS and WARNINGS. Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients (see 710 711 712 713 714 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. 715 716 717 718 Tryptophan — Five patients receiving Prozac in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. 719 720 Monoamine oxidase inhibitors — See CONTRAINDICATIONS. 721 Other drugs effective in the treatment of major depressive disorder — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see 722 723 724 725 726 727 728 Accumulation and slow elimination under CLINICAL PHARMACOLOGY, and Drugs metabolized by CYP2D6 under Drug Interactions). Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including Prozac, and the potential for serotonin syndrome, caution is advised when Prozac is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see 729 730 731 732 733 734 Serotonin Syndrome under WARNINGS). The concomitant use of Prozac with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Prozac with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see 735 736 737 738 Serotonin Syndrome under WARNINGS). Potential effects of coadministration of drugs tightly bound to plasma proteins — Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs (see 739 740 741 742 743 744 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs that interfere with hemostasis (NSAIDs, aspirin, warfarin, etc.) — Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluoxetine. 745 746 747 748 749 750 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Warfarin — Altered anticoagulant effects, including increased bleeding, have been reported when fluoxetine is coadministered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped. 751 752 753 Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. 754 755 756 757 758 759 760 Carcinogenesis, Mutagenesis, Impairment of Fertility There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) was not observed. Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m 761 762 763 764 2 basis], produced no evidence of carcinogenicity. Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. 765 766 767 768 Impairment of fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 2 basis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use). Pregnancy Pregnancy Category C — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects — Neonates exposed to Prozac and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Monoamine oxidase inhibitors under CONTRAINDICATIONS). Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 When treating a pregnant woman with Prozac during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. Labor and Delivery The effect of Prozac on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. Pediatric Use The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 (see CLINICAL TRIALS). The efficacy of Prozac for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 (see CLINICAL TRIALS). The safety and effectiveness in pediatric patients <8 years of age in major depressive disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major depressive disorder or OCD (see Pharmacokinetics under CLINICAL PHARMACOLOGY). The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse event profile observed in the 19-week major depressive disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS). Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. (See WARNINGS, Clinical Worsening and Suicide Risk.) Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis. In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain. Prozac is approved for use in pediatric patients with MDD and OCD (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Prozac in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use US fluoxetine clinical trials as of May 8, 1995 (10,782 patients) included 687 patients ≥65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric patients has been established (see CLINICAL TRIALS). For pharmacokinetic information in geriatric patients, see Age under CLINICAL PHARMACOLOGY. No overall differences in safety or 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. As with other SSRIs, fluoxetine has been associated with cases of clinically significant hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS). ADVERSE REACTIONS Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered Prozac in panic clinical trials. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled 926 clinical trials (excluding data from extensions of trials) — Table 2 enumerates the most common treatment-emergent adverse events associated with the use of Prozac (incidence of at least 5% for Prozac and at least twice that for placebo within at least 1 of the indications) for the treatment of major depressive disorder, OCD, and bulimia in US controlled clinical trials and panic disorder in US plus non-US controlled trials. Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more patients treated with Prozac and with incidence greater than placebo who participated in US major depressive disorder, OCD, and bulimia controlled clinical trials and US 927 928 929 930 931 932 933 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 plus non-US panic disorder controlled clinical trials. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2. 934 935 936 937 938 939 Table 2: Most Common Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Event Prozac (N=1728) Placebo (N=975) Prozac (N=266) Placebo (N=89) Prozac (N=450) Placebo (N=267) Prozac (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence2 2 -- -- -- 7 -- 1 -- Abnormal ejaculation2 -- -- 7 -- 7 -- 2 1 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. 940 941 942 943 944 945 946 2 Denominator used was for males only (N=690 Prozac major depressive disorder; N=410 placebo major depressive disorder; N=116 Prozac OCD; N=43 placebo OCD; N=14 Prozac bulimia; N=1 placebo bulimia; N=162 Prozac panic; N=121 placebo panic). -- Incidence less than 1%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Table 3: Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 947 948 1 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Event2 Prozac (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. 949 950 951 952 953 954 955 956 2 Included are events reported by at least 2% of patients taking Prozac, except the following events, which had an incidence on placebo ≥ Prozac (major depressive disorder, OCD, bulimia, and panic disorder combined): abdominal pain, abnormal dreams, accidental injury, back pain, cough increased, major depressive disorder (includes suicidal thoughts), dysmenorrhea, infection, myalgia, pain, paresthesia, pharyngitis, rhinitis, sinusitis. -- Incidence less than 1%. Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic 957 disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 4 lists the adverse events associated with discontinuation of Prozac treatment (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. 958 959 960 961 962 963 964 965 966 Table 4: Most Common Adverse Events Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) -- -- Rash (1%) -- -- 1 Includes US major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. 967 968 969 Other adverse events in pediatric patients (children and adolescents) — Treatment-emergent adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse events was generally similar to that seen in adult studies, as shown in Tables 2 and 3. However, the following adverse events (excluding those which appear in the body or footnotes of Tables 2 and 3 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. 970 971 972 973 974 975 976 977 978 979 980 981 982 The most common adverse event (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary event associated with discontinuation was collected. Events observed in Prozac Weekly clinical trials — Treatment-emergent adverse events in clinical trials with Prozac Weekly were similar to the adverse events reported by patients in clinical trials with Prozac daily. In a placebo-controlled clinical trial, more patients taking Prozac Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking Prozac 20 mg daily (10% versus 5%, respectively). 983 984 985 986 987 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US major depressive disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Other Events Observed in Clinical Trials Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking fluoxetine in US clinical trials as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 2 or 3 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to Prozac use was considered remote; and (4) events occurring in only 1 patient treated with Prozac and which did not have a substantial probability of being acutely life-threatening. Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients. Body as a Whole — Frequent: chest pain, chills; Infrequent: chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome1, photosensitivity reaction. Cardiovascular System — Frequent: hemorrhage, hypertension, palpitation; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. Digestive System — Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Endocrine System — Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 Hemic and Lymphatic System — Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia. Metabolic and Nutritional — Frequent: weight gain; Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. Musculoskeletal System — Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis. Nervous System — Frequent: agitation, amnesia, confusion, emotional lability, sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder2, psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor. Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor. Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect. Urogenital System — Frequent: urinary frequency; Infrequent: abortion3, albuminuria, amenorrhea3, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation3, fibrocystic breast3, hematuria, leukorrhea3, menorrhagia3, metrorrhagia3, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage3; Rare: breast engorgement, glycosuria, hypomenorrhea3, kidney pain, oliguria, priapism3, uterine hemorrhage3, uterine fibroids enlarged3. 1 Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome. 2 Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. 3 Adjusted for gender. Postintroduction Reports Voluntary reports of adverse events temporally associated with Prozac that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors. 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 DRUG ABUSE AND DEPENDENCE Controlled substance class — Prozac is not a controlled substance. Physical and psychological dependence — Prozac has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope. 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (see Management of Overdose). Management of Overdose Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS). Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 DOSAGE AND ADMINISTRATION 1168 1169 1170 Major Depressive Disorder Initial Treatment Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in major depressive disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. 1171 1172 1173 1174 1175 1176 1177 1178 A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of major depressive disorder, patients were administered fluoxetine doses of 10 to 20 mg/day (see 1179 1180 1181 1182 1183 1184 1185 1186 CLINICAL TRIALS). Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. All patients — As with other drugs effective in the treatment of major depressive disorder, the full effect may be delayed until 4 weeks of treatment or longer. 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Daily Dosing Systematic evaluation of Prozac in adult patients has shown that its efficacy in major depressive disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day (see CLINICAL TRIALS). Weekly Dosing Systematic evaluation of Prozac Weekly in adult patients has shown that its efficacy in major depressive disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment with Prozac 20 mg once daily. However, therapeutic equivalence of Prozac Weekly given on a once-weekly basis with Prozac 20 mg given daily for delaying time to relapse has not been established (see CLINICAL TRIALS). Weekly dosing with Prozac Weekly capsules is recommended to be initiated 7 days after the last daily dose of Prozac 20 mg (see Weekly dosing under CLINICAL PHARMACOLOGY). If satisfactory response is not maintained with Prozac Weekly, consider reestablishing a daily dosing regimen (see CLINICAL TRIALS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 Switching Patients to a Tricyclic Antidepressant (TCA) 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS, Drug Interactions). Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping Prozac before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS). Obsessive Compulsive Disorder Initial Treatment Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo (see 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 CLINICAL TRIALS). In 1 of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once-a-day (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 CLINICAL TRIALS). In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. All patients — As with the use of Prozac in the treatment of major depressive disorder, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment While there are no systematic studies that answer the question of how long to continue Prozac, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of Prozac after 13 weeks has not been documented in controlled trials, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 Bulimia Nervosa Initial Treatment In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo (see CLINICAL TRIALS). Only the 60-mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. As with the use of Prozac in the treatment of major depressive disorder and OCD, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment Systematic evaluation of continuing Prozac 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking Prozac 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment (see CLINICAL TRIALS). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Panic Disorder Initial Treatment In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of panic disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see CLINICAL TRIALS). Treatment should be initiated with a dose of 10 mg/day. After 1 week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with panic disorder. As with the use of Prozac in other indications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 Maintenance/Continuation Treatment 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 While there are no systematic studies that answer the question of how long to continue Prozac, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Prozac and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Prozac during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Prozac in the third trimester. Discontinuation of Treatment with Prozac Symptoms associated with discontinuation of Prozac and other SSRIs and SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. HOW SUPPLIED The following products are manufactured by Eli Lilly and Company for Dista Products Company. Prozac® Pulvules®, USP, are available in: The 10-mg1, Pulvule is opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body: NDC 0777-3104-02 (PU31042) - Bottles of 100 The 20-mg1 Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body: NDC 0777-3105-30 (PU31052) - Bottles of 30 NDC 0777-3105-02 (PU31052) - Bottles of 100 NDC 0777-3105-07 (PU31052) - Bottles of 2000 The 40-mg1 Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body: NDC 0777-3107-30 (PU31072) - Bottles of 30 The following is manufactured by OSG Norwich Pharmaceuticals, Inc., North Norwich, NY, 13814, for Dista Products Company: Liquid, Oral Solution is available in: 20 mg1 per 5 mL with mint flavor: NDC 0777-5120-58 (MS-51203) - Bottles of 120 mL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 The following product is manufactured and distributed by Eli Lilly and Company: Prozac® Weekly™ Capsules are available in: The 90-mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) - Blister package of 4 ______________________ 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1 Fluoxetine base equivalent. 2 Protect from light. 3 Dispense in a tight, light-resistant container. Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). ANIMAL TOXICOLOGY Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. Literature revised June 21, 2007 Eli Lilly and Company Indianapolis, IN 46285, USA www.lilly.com PV 5324 DPP PRINTED IN USA 1341 Medication Guide 1342 Antidepressant Medicines, Depression and other Serious Mental 1343 Illnesses, and Suicidal Thoughts or Actions 1344 1345 1346 1347 1348 1349 1350 Read the Medication Guide that comes with your 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 1351 medicines, depression and other serious mental illnesses, and suicidal thoughts 1352 or actions? 1353 1354 1355 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 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. 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 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 What else do I need to know about antidepressant medicines? 1385 1386 1387 1388 1389 1390 1391 • 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:04.469980	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018936s081s082,020101s037,021235s009lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 81}
11,375	1 PV 5326 DPP 1 PROZAC® 2 FLUOXETINE CAPSULES, USP 3 FLUOXETINE ORAL SOLUTION, USP 4 FLUOXETINE DELAYED-RELEASE CAPSULES, USP 5 WARNING 6 Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to 7 placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young 8 adults in short-term studies of major depressive disorder (MDD) and other psychiatric 9 disorders. Anyone considering the use of Prozac or any other antidepressant in a child, 10 adolescent, or young adult must balance this risk with the clinical need. Short-term studies 11 did not show an increase in the risk of suicidality with antidepressants compared to 12 placebo in adults beyond age 24; there was a reduction in risk with antidepressants 13 compared to placebo in adults aged 65 and older. Depression and certain other psychiatric 14 disorders are themselves associated with increases in the risk of suicide. Patients of all ages 15 who are started on antidepressant therapy should be monitored appropriately and 16 observed closely for clinical worsening, suicidality, or unusual changes in behavior. 17 Families and caregivers should be advised of the need for close observation and 18 communication with the prescriber. Prozac is approved for use in pediatric patients with 19 MDD and obsessive compulsive disorder (OCD). (See WARNINGS, Clinical Worsening 20 and Suicide Risk, PRECAUTIONS, Information for Patients, and PRECAUTIONS, 21 Pediatric Use.) 22 DESCRIPTION 23 Prozac® (fluoxetine capsules, USP and fluoxetine oral solution, USP) is a psychotropic drug 24 for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder 25 (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α- 26 trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of 27 C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: 28 29 Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL 30 in water. 31 Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 32 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The Pulvules also contain starch, 33 gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- and 20-mg 34 Pulvules also contain FD&C Blue No. 1, and the 40-mg Pulvule also contains FD&C Blue No. 1 35 and FD&C Yellow No. 6. 36 The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 μmol) of 37 fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, 38 and sucrose. 39 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Prozac Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of 40 fluoxetine hydrochloride equivalent to 90 mg (291 μmol) of fluoxetine. The capsules also 41 contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate 42 succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, 43 and other inactive ingredients. 44 CLINICAL PHARMACOLOGY 45 Pharmacodynamics 46 The antidepressant, antiobsessive compulsive, and antibulimic actions of fluoxetine are 47 presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically 48 relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into 49 human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake 50 inhibitor of serotonin than of norepinephrine. 51 Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized 52 to be associated with various anticholinergic, sedative, and cardiovascular effects of classical 53 tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors 54 from brain tissue much less potently in vitro than do the tricyclic drugs. 55 Absorption, Distribution, Metabolism, and Excretion 56 Systemic bioavailability — In man, following a single oral 40-mg dose, peak plasma 57 concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. 58 The Pulvule, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are 59 bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although 60 it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, 61 fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayed-release 62 formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the 63 gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of 64 absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. 65 Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 66 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and 67 α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has 68 not been fully evaluated, but may be important (see PRECAUTIONS). 69 Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine 70 enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake 71 inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is 72 eliminated more slowly and is the predominant enantiomer present in plasma at steady state. 73 Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a 74 number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is 75 formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and 76 selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or 77 S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of 78 serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive 79 metabolites excreted by the kidney. 80 Clinical issues related to metabolism/elimination — The complexity of the metabolism of 81 fluoxetine has several consequences that may potentially affect fluoxetine’s clinical use. 82 Variability in metabolism — A subset (about 7%) of the population has reduced activity of the 83 drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as 84 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study 85 involving labeled and unlabeled enantiomers administered as a racemate, these individuals 86 metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of 87 S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The 88 metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with 89 normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active 90 enantiomers was not significantly greater among poor metabolizers. Thus, the net 91 pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways 92 (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine 93 achieves a steady-state concentration rather than increasing without limit. 94 Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs 95 and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, 96 concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may 97 lead to drug interactions (see Drug Interactions under PRECAUTIONS). 98 Accumulation and slow elimination — The relatively slow elimination of fluoxetine 99 (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic 100 administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after 101 acute and chronic administration), leads to significant accumulation of these active species in 102 chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days 103 of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and 104 norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of 105 fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s 106 metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear 107 pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple 108 dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 109 weeks. 110 The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing 111 is stopped, active drug substance will persist in the body for weeks (primarily depending on 112 individual patient characteristics, previous dosing regimen, and length of previous therapy at 113 discontinuation). This is of potential consequence when drug discontinuation is required or when 114 drugs are prescribed that might interact with fluoxetine and norfluoxetine following the 115 discontinuation of Prozac. 116 Weekly dosing — Administration of Prozac Weekly once weekly results in increased 117 fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared 118 with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 119 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of 120 clinical response. Peak concentrations from once-weekly doses of Prozac Weekly capsules of 121 fluoxetine are in the range of the average concentration for 20-mg once-daily dosing. Average 122 trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the 123 concentrations maintained by 20-mg once-daily dosing. Average steady-state concentrations of 124 either once-daily or once-weekly dosing are in relative proportion to the total dose administered. 125 Average steady-state fluoxetine concentrations are approximately 50% lower following the 126 once-weekly regimen compared with the once-daily regimen. 127 Cmax for fluoxetine following the 90-mg dose was approximately 1.7-fold higher than the Cmax 128 value for the established 20-mg once-daily regimen following transition the next day to the 129 once-weekly regimen. In contrast, when the first 90-mg once-weekly dose and the last 20-mg 130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient 131 increase in the average steady-state concentrations of fluoxetine observed following transition 132 the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better 133 to separate the first 90-mg weekly dose and the last 20-mg once-daily dose by 1 week (see 134 DOSAGE AND ADMINISTRATION). 135 Liver disease — As might be predicted from its primary site of metabolism, liver impairment 136 can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in 137 a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen 138 in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean 139 duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal 140 subjects. This suggests that the use of fluoxetine in patients with liver disease must be 141 approached with caution. If fluoxetine is administered to patients with liver disease, a lower or 142 less frequent dose should be used (see PRECAUTIONS and DOSAGE AND 143 ADMINISTRATION). 144 Renal disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg 145 once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma 146 concentrations comparable with those seen in patients with normal renal function. While the 147 possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels 148 in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely 149 necessary in renally impaired patients (see Use in Patients with Concomitant Illness under 150 PRECAUTIONS and DOSAGE AND ADMINISTRATION). 151 Age 152 Geriatric pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly 153 subjects (>65 years of age) did not differ significantly from that in younger normal subjects. 154 However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not 155 adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they 156 have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age 157 upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy 158 depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined 159 fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 160 weeks. No unusual age-associated pattern of adverse events was observed in those elderly 161 patients. 162 Pediatric pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were 163 evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) 164 diagnosed with major depressive disorder or obsessive compulsive disorder (OCD). Fluoxetine 165 20 mg/day was administered for up to 62 days. The average steady-state concentrations of 166 fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, 167 respectively). The average norfluoxetine steady-state concentrations in these children were 168 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be 169 almost entirely explained by differences in weight. No gender-associated difference in fluoxetine 170 pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma 171 concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed 172 with major depressive disorder. 173 Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in 174 children relative to adults; however, these concentrations were within the range of concentrations 175 observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated 176 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 177 4 weeks of daily dosing. 178 CLINICAL TRIALS 179 Major Depressive Disorder 180 Daily Dosing 181 Adult — The efficacy of Prozac for the treatment of patients with major depressive disorder 182 (≥18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac was 183 shown to be significantly more effective than placebo as measured by the Hamilton Depression 184 Rating Scale (HAM-D). Prozac was also significantly more effective than placebo on the 185 HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. 186 Two 6-week controlled studies (N=671, randomized) comparing Prozac 20 mg and placebo 187 have shown Prozac 20 mg daily to be effective in the treatment of elderly patients (≥60 years of 188 age) with major depressive disorder. In these studies, Prozac produced a significantly higher rate 189 of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a 190 total endpoint HAM-D score of ≤8. Prozac was well tolerated and the rate of treatment 191 discontinuations due to adverse events did not differ between Prozac (12%) and placebo (9%). 192 A study was conducted involving depressed outpatients who had responded (modified 193 HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of 194 major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week 195 open-treatment phase on Prozac 20 mg/day. These patients (N=298) were randomized to 196 continuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), a 197 statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis 198 of major depressive disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was 199 observed for patients taking Prozac compared with those on placebo. 200 Pediatric (children and adolescents) — The efficacy of Prozac 20 mg/day for the treatment of 201 major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to 202 <13, 145 adolescents ages 13 to ≤18) has been studied in two 8- to 9-week placebo-controlled 203 clinical trials. 204 In both studies independently, Prozac produced a statistically significantly greater mean 205 change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline 206 to endpoint than did placebo. 207 Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness 208 on the basis of age or gender. 209 Weekly dosing for maintenance/continuation treatment 210 A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for 211 major depressive disorder who had responded (defined as having a modified HAMD-17 score of 212 ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for major depressive disorder) for 213 3 consecutive weeks at the end of 13 weeks of open-label treatment with Prozac 20 mg once 214 daily. These patients were randomized to double-blind, once-weekly continuation treatment with 215 Prozac Weekly, Prozac 20 mg once daily, or placebo. Prozac Weekly once weekly and Prozac 216 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of 217 depressive symptoms) compared with placebo for a period of 25 weeks. However, the 218 equivalence of these 2 treatments during continuation therapy has not been established. 219 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Obsessive Compulsive Disorder 220 Adult — The effectiveness of Prozac for the treatment of obsessive compulsive disorder 221 (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of 222 adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once-a-day 223 schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD 224 (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale 225 (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced 226 mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit 227 reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean 228 reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit 229 reduction for placebo patients. While there was no indication of a dose-response relationship for 230 effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically 231 better responses in the 2 higher dose groups. The following table provides the outcome 232 classification by treatment group on the Clinical Global Impression (CGI) improvement scale for 233 Studies 1 and 2 combined: 234 235 Outcome Classification (%) on CGI Improvement Scale for 236 Completers in Pool of Two OCD Studies 237 Prozac Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% 238 Exploratory analyses for age and gender effects on outcome did not suggest any differential 239 responsiveness on the basis of age or sex. 240 Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients 241 (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD, 242 patients received Prozac 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose 243 was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and 244 tolerability. Prozac produced a statistically significantly greater mean change from baseline to 245 endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive 246 Scale (CY-BOCS). 247 Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of 248 age or gender. 249 Bulimia Nervosa 250 The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8-week and 251 one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria 252 for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of Prozac or placebo 253 in the morning. Patients in the 16-week study received a fixed Prozac dose of 60 mg/day (once a 254 day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median 255 binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, 256 respectively. In these 3 studies, Prozac 60 mg, but not 20 mg, was statistically significantly 257 superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The 258 statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 259 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 and persisted throughout each study. The Prozac-related reduction in bulimic episodes appeared 260 to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. 261 In each of these 3 studies, the treatment effect, as measured by differences between Prozac 262 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at 263 endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for 264 vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in 265 patients with higher baseline frequencies. Although some patients achieved freedom from 266 binge-eating and purging as a result of treatment, for the majority, the benefit was a partial 267 reduction in the frequency of binge-eating and purging. 268 In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging 269 subtype, who had responded during a single-blind, 8-week acute treatment phase with Prozac 270 60 mg/day, were randomized to continuation of Prozac 60 mg/day or placebo, for up to 52 weeks 271 of observation for relapse. Response during the single-blind phase was defined by having 272 achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during 273 the double-blind phase was defined as a persistent return to baseline vomiting frequency or 274 physician judgment that the patient had relapsed. Patients receiving continued Prozac 60 mg/day 275 experienced a significantly longer time to relapse over the subsequent 52 weeks compared with 276 those receiving placebo. 277 Panic Disorder 278 The effectiveness of Prozac in the treatment of panic disorder was demonstrated in 2 279 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a 280 primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia. 281 Study 1 (N=180 randomized) was a 12-week flexible-dose study. Prozac was initiated at 282 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on 283 the basis of clinical response and tolerability. A statistically significantly greater percentage of 284 Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 285 42% versus 28%, respectively. 286 Study 2 (N=214 randomized) was a 12-week flexible-dose study. Prozac was initiated at 287 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on 288 the basis of clinical response and tolerability. A statistically significantly greater percentage of 289 Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 290 62% versus 44%, respectively. 291 INDICATIONS AND USAGE 292 Major Depressive Disorder 293 Prozac is indicated for the treatment of major depressive disorder. 294 Adult — The efficacy of Prozac was established in 5- and 6-week trials with depressed adult 295 and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the 296 DSM-III (currently DSM-IV) category of major depressive disorder (see CLINICAL TRIALS). 297 A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly 298 every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily 299 functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of 300 interest in usual activities, significant change in weight and/or appetite, insomnia or 301 hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or 302 worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. 303 The effects of Prozac in hospitalized depressed patients have not been adequately studied. 304 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 The efficacy of Prozac 20 mg once daily in maintaining a response in major depressive 305 disorder for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) 306 was demonstrated in a placebo-controlled trial. 307 The efficacy of Prozac Weekly once weekly in maintaining a response in major depressive 308 disorder has been demonstrated in a placebo-controlled trial for up to 25 weeks following 309 open-label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38 310 weeks. However, it is unknown whether or not Prozac Weekly given on a once-weekly basis 311 provides the same level of protection from relapse as that provided by Prozac 20 mg daily 312 (see CLINICAL TRIALS). 313 Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was 314 established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose 315 diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive 316 disorder (see CLINICAL TRIALS). 317 The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended 318 periods should be reevaluated periodically. 319 Obsessive Compulsive Disorder 320 Adult — Prozac is indicated for the treatment of obsessions and compulsions in patients with 321 obsessive compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or 322 compulsions cause marked distress, are time-consuming, or significantly interfere with social or 323 occupational functioning. 324 The efficacy of Prozac was established in 13-week trials with obsessive compulsive outpatients 325 whose diagnoses corresponded most closely to the DSM-III-R category of OCD (see CLINICAL 326 TRIALS). 327 OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images 328 (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors 329 (compulsions) that are recognized by the person as excessive or unreasonable. 330 The effectiveness of Prozac in long-term use, i.e., for more than 13 weeks, has not been 331 systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use 332 Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug 333 for the individual patient (see DOSAGE AND ADMINISTRATION). 334 Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was 335 established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in 336 DSM-IV (see CLINICAL TRIALS). 337 Bulimia Nervosa 338 Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with 339 moderate to severe bulimia nervosa. 340 The efficacy of Prozac was established in 8- to 16-week trials for adult outpatients with 341 moderate to severe bulimia nervosa, i.e., at least 3 bulimic episodes per week for 6 months (see 342 CLINICAL TRIALS). 343 The efficacy of Prozac 60 mg/day in maintaining a response, in patients with bulimia who 344 responded during an 8-week acute treatment phase while taking Prozac 60 mg/day and were then 345 observed for relapse during a period of up to 52 weeks, was demonstrated in a placebo-controlled 346 trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Prozac for 347 extended periods should periodically reevaluate the long-term usefulness of the drug for the 348 individual patient (see DOSAGE AND ADMINISTRATION). 349 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Panic Disorder 350 Prozac is indicated for the treatment of panic disorder, with or without agoraphobia, as defined 351 in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks, and 352 associated concern about having additional attacks, worry about the implications or 353 consequences of the attacks, and/or a significant change in behavior related to the attacks. 354 The efficacy of Prozac was established in two 12-week clinical trials in patients whose 355 diagnoses corresponded to the DSM-IV category of panic disorder (see CLINICAL TRIALS). 356 Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a 357 discrete period of intense fear or discomfort in which 4 or more of the following symptoms 358 develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or 359 accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath 360 or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal 361 distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear of 362 dying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes. 363 The effectiveness of Prozac in long-term use, i.e., for more than 12 weeks, has not been 364 established in placebo-controlled trials. Therefore, the physician who elects to use Prozac for 365 extended periods should periodically reevaluate the long-term usefulness of the drug for the 366 individual patient (see DOSAGE AND ADMINISTRATION). 367 CONTRAINDICATIONS 368 Prozac is contraindicated in patients known to be hypersensitive to it. 369 Monoamine oxidase inhibitors — There have been reports of serious, sometimes fatal, 370 reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid 371 fluctuations of vital signs, and mental status changes that include extreme agitation progressing 372 to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase 373 inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started 374 on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. 375 Therefore, Prozac should not be used in combination with an MAOI, or within a minimum of 14 376 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have 377 very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has 378 been prescribed chronically and/or at higher doses (see Accumulation and slow elimination 379 under CLINICAL PHARMACOLOGY)] should be allowed after stopping Prozac before starting 380 an MAOI. 381 Pimozide — Concomitant use in patients taking pimozide is contraindicated (see 382 PRECAUTIONS). 383 Thioridazine — Thioridazine should not be administered with Prozac or within a minimum of 384 5 weeks after Prozac has been discontinued (see WARNINGS). 385 WARNINGS 386 Clinical Worsening and Suicide Risk — Patients with major depressive disorder (MDD), 387 both adult and pediatric, may experience worsening of their depression and/or the emergence of 388 suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they 389 are taking antidepressant medications, and this risk may persist until significant remission 390 occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these 391 disorders themselves are the strongest predictors of suicide. There has been a long-standing 392 concern, however, that antidepressants may have a role in inducing worsening of depression and 393 the emergence of suicidality in certain patients during the early phases of treatment. Pooled 394 analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) 395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in 396 children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and 397 other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality 398 with antidepressants compared to placebo in adults beyond age 24; there was a reduction with 399 antidepressants compared to placebo in adults aged 65 and older. 400 The pooled analyses of placebo-controlled trials in children and adolescents with MDD, 401 obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 402 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of 403 placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 404 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 405 patients. There was considerable variation in risk of suicidality among drugs, but a tendency 406 toward an increase in the younger patients for almost all drugs studied. There were differences in 407 absolute risk of suicidality across the different indications, with the highest incidence in MDD. 408 The risk differences (drug versus placebo), however, were relatively stable within age strata and 409 across indications. These risk differences (drug-placebo difference in the number of cases of 410 suicidality per 1000 patients treated) are provided in Table 1. 411 412 Table 1 413 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 414 No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but 415 the number was not sufficient to reach any conclusion about drug effect on suicide. 416 It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several 417 months. However, there is substantial evidence from placebo-controlled maintenance trials in 418 adults with depression that the use of antidepressants can delay the recurrence of depression. 419 All patients being treated with antidepressants for any indication should be monitored 420 appropriately and observed closely for clinical worsening, suicidality, and unusual changes 421 in behavior, especially during the initial few months of a course of drug therapy, or at times 422 of dose changes, either increases or decreases. 423 The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, 424 aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have 425 been reported in adult and pediatric patients being treated with antidepressants for major 426 depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. 427 Although a causal link between the emergence of such symptoms and either the worsening of 428 depression and/or the emergence of suicidal impulses has not been established, there is concern 429 that such symptoms may represent precursors to emerging suicidality. 430 Consideration should be given to changing the therapeutic regimen, including possibly 431 discontinuing the medication, in patients whose depression is persistently worse, or who are 432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 experiencing emergent suicidality or symptoms that might be precursors to worsening depression 433 or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the 434 patient’s presenting symptoms. 435 If the decision has been made to discontinue treatment, medication should be tapered, as 436 rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with 437 certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, 438 Discontinuation of Treatment with Prozac, for a description of the risks of discontinuation of 439 Prozac). 440 Families and caregivers of patients being treated with antidepressants for major 441 depressive disorder or other indications, both psychiatric and nonpsychiatric, should be 442 alerted about the need to monitor patients for the emergence of agitation, irritability, 443 unusual changes in behavior, and the other symptoms described above, as well as the 444 emergence of suicidality, and to report such symptoms immediately to health care 445 providers. Such monitoring should include daily observation by families and caregivers. 446 Prescriptions for Prozac should be written for the smallest quantity of capsules, or liquid 447 consistent with good patient management, in order to reduce the risk of overdose. 448 It should be noted that Prozac is approved in the pediatric population only for major depressive 449 disorder and obsessive compulsive disorder. 450 Screening Patients for Bipolar Disorder — A major depressive episode may be the initial 451 presentation of bipolar disorder. It is generally believed (though not established in controlled 452 trials) that treating such an episode with an antidepressant alone may increase the likelihood of 453 precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the 454 symptoms described above represent such a conversion is unknown. However, prior to initiating 455 treatment with an antidepressant, patients with depressive symptoms should be adequately 456 screened to determine if they are at risk for bipolar disorder; such screening should include a 457 detailed psychiatric history, including a family history of suicide, bipolar disorder, and 458 depression. It should be noted that Prozac is not approved for use in treating bipolar depression. 459 Rash and Possibly Allergic Events — In US fluoxetine clinical trials as of May 8, 1995, 7% 460 of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash 461 and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from 462 treatment because of the rash and/or systemic signs or symptoms associated with the rash. 463 Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, 464 edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild 465 transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine 466 and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these 467 events were reported to recover completely. 468 In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous 469 systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to 470 have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was 471 considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic 472 syndromes suggestive of serum sickness. 473 Since the introduction of Prozac, systemic events, possibly related to vasculitis and including 474 lupus-like syndrome, have developed in patients with rash. Although these events are rare, they 475 may be serious, involving the lung, kidney, or liver. Death has been reported to occur in 476 association with these systemic events. 477 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria 478 alone and in combination, have been reported. 479 Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, 480 have been reported rarely. These events have occurred with dyspnea as the only preceding 481 symptom. 482 Whether these systemic events and rash have a common underlying cause or are due to 483 different etiologies or pathogenic processes is not known. Furthermore, a specific underlying 484 immunologic basis for these events has not been identified. Upon the appearance of rash or of 485 other possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac 486 should be discontinued. 487 Serotonin Syndrome — The development of a potentially life-threatening serotonin syndrome 488 may occur with SNRIs and SSRIs, including Prozac treatment, particularly with concomitant use 489 of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin 490 (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., 491 agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, 492 hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or 493 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). 494 The concomitant use of Prozac with MAOIs intended to treat depression is contraindicated (see 495 CONTRAINDICATIONS and Drug Interactions under PRECAUTIONS). 496 If concomitant treatment Prozac with a 5-hydroxytryptamine receptor agonist (triptan) is 497 clinically warranted, careful observation of the patient is advised, particularly during treatment 498 initiation and dose increases (see Drug Interactions under PRECAUTIONS). 499 The concomitant use of Prozac with serotonin precursors (such as tryptophan) is not 500 recommended (see Drug Interactions under PRECAUTIONS). 501 Potential Interaction with Thioridazine — In a study of 19 healthy male subjects, which 502 included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of 503 thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the 504 slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin 505 hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study 506 suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will 507 produce elevated plasma levels of thioridazine (see PRECAUTIONS). 508 Thioridazine administration produces a dose-related prolongation of the QTc interval, which is 509 associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, 510 and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of 511 thioridazine metabolism (see CONTRAINDICATIONS). 512 PRECAUTIONS 513 General 514 Abnormal Bleeding — SSRIs and SNRIs, including fluoxetine, may increase the risk of 515 bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and 516 other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control 517 and cohort design) have demonstrated an association between use of drugs that interfere with 518 serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to 519 SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to 520 life-threatening hemorrhages. 521 Patients should be cautioned about the risk of bleeding associated with the concomitant use of 522 fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation (see Drug Interactions). 523 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Anxiety and Insomnia — In US placebo-controlled clinical trials for major depressive 524 disorder, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with 525 placebo reported anxiety, nervousness, or insomnia. 526 In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients 527 treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of 528 patients treated with Prozac and in 7% of patients treated with placebo. 529 In US placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of 530 patients treated with Prozac 60 mg, and 13% of patients treated with placebo. Anxiety and 531 nervousness were reported, respectively, in 15% and 11% of patients treated with Prozac 60 mg 532 and in 9% and 5% of patients treated with placebo. 533 Among the most common adverse events associated with discontinuation (incidence at least 534 twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event 535 associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety 536 (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% 537 in major depressive disorder) (see Table 4). 538 Altered Appetite and Weight — Significant weight loss, especially in underweight depressed 539 or bulimic patients may be an undesirable result of treatment with Prozac. 540 In US placebo-controlled clinical trials for major depressive disorder, 11% of patients treated 541 with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). 542 Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated 543 with placebo. However, only rarely have patients discontinued treatment with Prozac because of 544 anorexia or weight loss (see also Pediatric Use under PRECAUTIONS). 545 In US placebo-controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% 546 of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued 547 treatment with Prozac because of anorexia (see also Pediatric Use under PRECAUTIONS). 548 In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac 549 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients 550 treated with Prozac 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients 551 treated with placebo in the 16-week double-blind trial. Weight change should be monitored 552 during therapy. 553 Activation of Mania/Hypomania — In US placebo-controlled clinical trials for major 554 depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Prozac and 555 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a 556 small proportion of patients with Major Affective Disorder treated with other marketed drugs 557 effective in the treatment of major depressive disorder (see also Pediatric Use under 558 PRECAUTIONS). 559 In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of 560 patients treated with Prozac and no patients treated with placebo. No patients reported 561 mania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinical 562 trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see also Pediatric 563 Use under PRECAUTIONS). 564 Hyponatremia — Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, 565 including Prozac. In many cases, this hyponatremia appears to be the result of the syndrome of 566 inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 567 110 mmol/L have been reported and appeared to be reversible when Prozac was discontinued. 568 Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, 569 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 patients taking diuretics or who are otherwise volume depleted may be at greater risk (see 570 Geriatric Use). Discontinuation of Prozac should be considered in patients with symptomatic 571 hyponatremia and appropriate medical intervention should be instituted. 572 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory 573 impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or 574 acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, 575 and death. 576 Seizures — In US placebo-controlled clinical trials for major depressive disorder, convulsions 577 (or events described as possibly having been seizures) were reported in 0.1% of patients treated 578 with Prozac and 0.2% of patients treated with placebo. No patients reported convulsions in US 579 placebo-controlled clinical trials for either OCD or bulimia. In all US Prozac clinical trials as of 580 May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar 581 to that associated with other marketed drugs effective in the treatment of major depressive 582 disorder. Prozac should be introduced with care in patients with a history of seizures. 583 The Long Elimination Half-Lives of Fluoxetine and its Metabolites — Because of the long 584 elimination half-lives of the parent drug and its major active metabolite, changes in dose will not 585 be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose 586 and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND 587 ADMINISTRATION). 588 Use in Patients with Concomitant Illness — Clinical experience with Prozac in patients with 589 concomitant systemic illness is limited. Caution is advisable in using Prozac in patients with 590 diseases or conditions that could affect metabolism or hemodynamic responses. 591 Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent 592 history of myocardial infarction or unstable heart disease. Patients with these diagnoses were 593 systematically excluded from clinical studies during the product’s premarket testing. However, 594 the electrocardiograms of 312 patients who received Prozac in double-blind trials were 595 retrospectively evaluated; no conduction abnormalities that resulted in heart block were 596 observed. The mean heart rate was reduced by approximately 3 beats/min. 597 In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, 598 norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A 599 lower or less frequent dose should be used in patients with cirrhosis. 600 Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or 601 norfluoxetine in plasma (see Renal disease under CLINICAL PHARMACOLOGY). Use of a 602 lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE 603 AND ADMINISTRATION). 604 In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred 605 during therapy with Prozac, and hyperglycemia has developed following discontinuation of the 606 drug. As is true with many other types of medication when taken concurrently by patients with 607 diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with 608 Prozac is instituted or discontinued. 609 Interference with Cognitive and Motor Performance — Any psychoactive drug may impair 610 judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous 611 machinery, including automobiles, until they are reasonably certain that the drug treatment does 612 not affect them adversely. 613 Discontinuation of Treatment with Prozac — During marketing of Prozac and other SSRIs 614 and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous 615 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 reports of adverse events occurring upon discontinuation of these drugs, particularly when 616 abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory 617 disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, 618 lethargy, emotional lability, insomnia, and hypomania. While these events are generally 619 self-limiting, there have been reports of serious discontinuation symptoms. Patients should be 620 monitored for these symptoms when discontinuing treatment with Prozac. A gradual reduction in 621 the dose rather than abrupt cessation is recommended whenever possible. If intolerable 622 symptoms occur following a decrease in the dose or upon discontinuation of treatment, then 623 resuming the previously prescribed dose may be considered. Subsequently, the physician may 624 continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine 625 concentration decrease gradually at the conclusion of therapy, which may minimize the risk of 626 discontinuation symptoms with this drug (see DOSAGE AND ADMINISTRATION). 627 Information for Patients 628 Prescribers or other health professionals should inform patients, their families, and their 629 caregivers about the benefits and risks associated with treatment with Prozac and should counsel 630 them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, 631 Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available 632 for Prozac. The prescriber or health professional should instruct patients, their families, and their 633 caregivers to read the Medication Guide and should assist them in understanding its contents. 634 Patients should be given the opportunity to discuss the contents of the Medication Guide and to 635 obtain answers to any questions they may have. The complete text of the Medication Guide is 636 reprinted at the end of this document. 637 Patients should be advised of the following issues and asked to alert their prescriber if these 638 occur while taking Prozac. 639 Clinical Worsening and Suicide Risk — Patients, their families, and their caregivers should 640 be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, 641 irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), 642 hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal 643 ideation, especially early during antidepressant treatment and when the dose is adjusted up or 644 down. Families and caregivers of patients should be advised to look for the emergence of such 645 symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be 646 reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in 647 onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be 648 associated with an increased risk for suicidal thinking and behavior and indicate a need for very 649 close monitoring and possibly changes in the medication. 650 Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome 651 with the concomitant use of Prozac and triptans, tramadol or other serotonergic agents. 652 Because Prozac may impair judgment, thinking, or motor skills, patients should be advised to 653 avoid driving a car or operating hazardous machinery until they are reasonably certain that their 654 performance is not affected. 655 Patients should be advised to inform their physician if they are taking or plan to take any 656 prescription or over-the-counter drugs, or alcohol. 657 Abnormal Bleeding— Patients should be cautioned about the concomitant use of fluoxetine 658 and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of 659 psychotropic drugs that interfere with serotonin reuptake and these agents have been associated 660 with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). 661 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Patients should be advised to notify their physician if they become pregnant or intend to 662 become pregnant during therapy. 663 Patients should be advised to notify their physician if they are breast-feeding an infant. 664 Patients should be advised to notify their physician if they develop a rash or hives. 665 Laboratory Tests 666 There are no specific laboratory tests recommended. 667 Drug Interactions 668 As with all drugs, the potential for interaction by a variety of mechanisms (e.g., 669 pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see 670 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). 671 Drugs metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make 672 individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. 673 Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including 674 certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), 675 and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with 676 caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system 677 and that have a relatively narrow therapeutic index (see list below) should be initiated at the low 678 end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the 679 previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If 680 fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by 681 CYP2D6, the need for decreased dose of the original medication should be considered. Drugs 682 with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, 683 vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death 684 potentially associated with elevated plasma levels of thioridazine, thioridazine should not be 685 administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been 686 discontinued (see CONTRAINDICATIONS and WARNINGS). 687 Drugs metabolized by CYP3A4 — In an in vivo interaction study involving coadministration 688 of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma 689 terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies 690 have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more 691 potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for 692 this enzyme, including astemizole, cisapride, and midazolam. These data indicate that 693 fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. 694 CNS active drugs — The risk of using Prozac in combination with other CNS active drugs has 695 not been systematically evaluated. Nonetheless, caution is advised if the concomitant 696 administration of Prozac and such drugs is required. In evaluating individual cases, consideration 697 should be given to using lower initial doses of the concomitantly administered drugs, using 698 conservative titration schedules, and monitoring of clinical status (see Accumulation and slow 699 elimination under CLINICAL PHARMACOLOGY). 700 Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed 701 elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following 702 initiation of concomitant fluoxetine treatment. 703 Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or 704 pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of 705 haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. 706 Clinical studies of pimozide with other antidepressants demonstrate an increase in drug 707 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not 708 been conducted, the potential for drug interactions or QTc prolongation warrants restricting the 709 concurrent use of pimozide and Prozac. Concomitant use of Prozac and pimozide is 710 contraindicated (see CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS 711 and WARNINGS. 712 Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in 713 some patients (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). 714 Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma 715 concentrations and in further psychomotor performance decrement due to increased alprazolam 716 levels. 717 Lithium — There have been reports of both increased and decreased lithium levels when 718 lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased 719 serotonergic effects have been reported. Lithium levels should be monitored when these drugs 720 are administered concomitantly. 721 Tryptophan — Five patients receiving Prozac in combination with tryptophan experienced 722 adverse reactions, including agitation, restlessness, and gastrointestinal distress. 723 Monoamine oxidase inhibitors — See CONTRAINDICATIONS. 724 Other drugs effective in the treatment of major depressive disorder — In 2 studies, previously 725 stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold 726 when fluoxetine has been administered in combination. This influence may persist for 3 weeks or 727 longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and 728 plasma TCA concentrations may need to be monitored temporarily when fluoxetine is 729 coadministered or has been recently discontinued (see Accumulation and slow elimination under 730 CLINICAL PHARMACOLOGY, and Drugs metabolized by CYP2D6 under Drug Interactions). 731 Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including 732 Prozac, and the potential for serotonin syndrome, caution is advised when Prozac is 733 coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such 734 as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, 735 or St. John’s Wort (see Serotonin Syndrome under WARNINGS). The concomitant use of 736 Prozac with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). 737 Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an 738 SSRI and a triptan. If concomitant treatment of Prozac with a triptan is clinically warranted, 739 careful observation of the patient is advised, particularly during treatment initiation and dose 740 increases (see Serotonin Syndrome under WARNINGS). 741 Potential effects of coadministration of drugs tightly bound to plasma proteins — Because 742 fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking 743 another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in 744 plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may 745 result from displacement of protein-bound fluoxetine by other tightly-bound drugs (see 746 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). 747 Drugs that interfere with hemostasis (e.g., NSAIDs, Aspirin, Warfarin) — Serotonin release by 748 platelets plays an important role in hemostasis. Epidemiological studies of the case-control and 749 cohort design that have demonstrated an association between use of psychotropic drugs that 750 interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also 751 shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered 752 anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs 753 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 are coadministered with warfarin. Patients receiving warfarin therapy should be carefully 754 monitored when fluoxetine is initiated or discontinued. 755 Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the 756 combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in 757 patients on fluoxetine receiving ECT treatment. 758 Carcinogenesis, Mutagenesis, Impairment of Fertility 759 There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. 760 Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times 761 the MRHD on a mg/m2 basis) was not observed. 762 Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at 763 doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, 764 the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no 765 evidence of carcinogenicity. 766 Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects 767 based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat 768 hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese 769 hamster bone marrow cells. 770 Impairment of fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 771 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that 772 fluoxetine had no adverse effects on fertility (see Pediatric Use). 773 Pregnancy 774 Pregnancy Category C — In embryo-fetal development studies in rats and rabbits, there was 775 no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, 776 respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m2 basis) throughout 777 organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in 778 pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following 779 maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 780 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was 781 no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 782 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 783 times the MRHD on a mg/m2 basis). Prozac should be used during pregnancy only if the 784 potential benefit justifies the potential risk to the fetus. 785 Nonteratogenic Effects — Neonates exposed to Prozac and other SSRIs or serotonin and 786 norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed 787 complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such 788 complications can arise immediately upon delivery. Reported clinical findings have included 789 respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, 790 vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and 791 constant crying. These features are consistent with either a direct toxic effect of SSRIs and 792 SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the 793 clinical picture is consistent with serotonin syndrome (see Monoamine oxidase inhibitors under 794 CONTRAINDICATIONS). 795 Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent 796 pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the 797 general population and is associated with substantial neonatal morbidity and mortality. In a 798 retrospective case-control study of 377 women whose infants were born with PPHN and 836 799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 women whose infants were born healthy, the risk for developing PPHN was approximately 800 six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants 801 who had not been exposed to antidepressants during pregnancy. There is currently no 802 corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; 803 this is the first study that has investigated the potential risk. The study did not include enough 804 cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN 805 risk. 806 When treating a pregnant woman with Prozac during the third trimester, the physician should 807 carefully consider both the potential risks and benefits of treatment (see DOSAGE AND 808 ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 809 women with a history of major depression who were euthymic at the beginning of pregnancy, 810 women who discontinued antidepressant medication during pregnancy were more likely to 811 experience a relapse of major depression than women who continued antidepressant medication. 812 Labor and Delivery 813 The effect of Prozac on labor and delivery in humans is unknown. However, because 814 fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse 815 effects on the newborn, fluoxetine should be used during labor and delivery only if the potential 816 benefit justifies the potential risk to the fetus. 817 Nursing Mothers 818 Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In 819 one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The 820 concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were 821 reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep 822 disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of 823 fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. 824 Pediatric Use 825 The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 826 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 (see 827 CLINICAL TRIALS). 828 The efficacy of Prozac for the treatment of OCD was demonstrated in one 13-week 829 placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 (see CLINICAL 830 TRIALS). 831 The safety and effectiveness in pediatric patients <8 years of age in major depressive disorder 832 and <7 years of age in OCD have not been established. 833 Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major 834 depressive disorder or OCD (see Pharmacokinetics under CLINICAL PHARMACOLOGY). 835 The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 836 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies 837 with fluoxetine. The longer-term adverse event profile observed in the 19-week major depressive 838 disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar 839 to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS). 840 Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out 841 of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. 842 Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the 843 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of 844 mania/hypomania is recommended. 845 As with other SSRIs, decreased weight gain has been observed in association with the use of 846 fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, 847 pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) 848 and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine 849 treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine 850 treatment for pediatric patients has not been systematically assessed for chronic treatment longer 851 than several months in duration. In particular, there are no studies that directly evaluate the 852 longer-term effects of fluoxetine on the growth, development, and maturation of children and 853 adolescent patients. Therefore, height and weight should be monitored periodically in pediatric 854 patients receiving fluoxetine. 855 (See WARNINGS, Clinical Worsening and Suicide Risk.) 856 Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive 857 toxicity, and impaired bone development, has been observed following exposure of juvenile 858 animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. 859 In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from 860 weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development 861 was delayed at all doses, and growth (body weight gain, femur length) was decreased during the 862 dosing period in animals receiving the highest dose. At the end of the treatment period, serum 863 levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high 864 doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle 865 degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and 866 hypospermia) was observed at the high dose. When animals were evaluated after a recovery 867 period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased 868 reactivity at all doses and learning deficit at the high dose) and reproductive functional 869 impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in 870 addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were 871 found in the high dose group, indicating that the reproductive organ effects seen at the end of 872 treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not 873 assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the 874 juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma 875 exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in 876 this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in 877 pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat 878 exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 879 times, respectively, pediatric exposure at the MRD. 880 A specific effect of fluoxetine on bone development has been reported in mice treated with 881 fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, 882 intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in 883 decreased bone mineral content and density. These doses did not affect overall growth (body 884 weight gain or femoral length). The doses administered to juvenile mice in this study are 885 approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) 886 basis. 887 In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early 888 postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors 889 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in 890 adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric 891 MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of 892 these findings to the approved pediatric use in humans is uncertain. 893 Prozac is approved for use in pediatric patients with MDD and OCD (see BOX WARNING 894 and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Prozac 895 in a child or adolescent must balance the potential risks with the clinical need. 896 Geriatric Use 897 US fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years 898 of age. The efficacy in geriatric patients has been established (see CLINICAL TRIALS). For 899 pharmacokinetic information in geriatric patients, see Age under CLINICAL 900 PHARMACOLOGY. No overall differences in safety or effectiveness were observed between 901 these subjects and younger subjects, and other reported clinical experience has not identified 902 differences in responses between the elderly and younger patients, but greater sensitivity of some 903 older individuals cannot be ruled out. SSRIs and SNRIs, including Prozac, have been associated 904 with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk 905 for this adverse event (see PRECAUTIONS, Hyponatremia). 906 ADVERSE REACTIONS 907 Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in 908 US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered 909 Prozac in panic clinical trials. Adverse events were recorded by clinical investigators using 910 descriptive terminology of their own choosing. Consequently, it is not possible to provide a 911 meaningful estimate of the proportion of individuals experiencing adverse events without first 912 grouping similar types of events into a limited (i.e., reduced) number of standardized event 913 categories. 914 In the tables and tabulations that follow, COSTART Dictionary terminology has been used to 915 classify reported adverse events. The stated frequencies represent the proportion of individuals 916 who experienced, at least once, a treatment-emergent adverse event of the type listed. An event 917 was considered treatment-emergent if it occurred for the first time or worsened while receiving 918 therapy following baseline evaluation. It is important to emphasize that events reported during 919 therapy were not necessarily caused by it. 920 The prescriber should be aware that the figures in the tables and tabulations cannot be used to 921 predict the incidence of side effects in the course of usual medical practice where patient 922 characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, 923 the cited frequencies cannot be compared with figures obtained from other clinical investigations 924 involving different treatments, uses, and investigators. The cited figures, however, do provide the 925 prescribing physician with some basis for estimating the relative contribution of drug and 926 nondrug factors to the side effect incidence rate in the population studied. 927 Incidence in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled 928 clinical trials (excluding data from extensions of trials) — Table 2 enumerates the most common 929 treatment-emergent adverse events associated with the use of Prozac (incidence of at least 5% for 930 Prozac and at least twice that for placebo within at least 1 of the indications) for the treatment of 931 major depressive disorder, OCD, and bulimia in US controlled clinical trials and panic disorder 932 in US plus non-US controlled trials. Table 3 enumerates treatment-emergent adverse events that 933 occurred in 2% or more patients treated with Prozac and with incidence greater than placebo who 934 participated in US major depressive disorder, OCD, and bulimia controlled clinical trials and US 935 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 plus non-US panic disorder controlled clinical trials. Table 3 provides combined data for the pool 936 of studies that are provided separately by indication in Table 2. 937 938 Table 2: Most Common Treatment-Emergent Adverse Events: Incidence in Major 939 Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical 940 Trials1 941 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Event Prozac (N=1728) Placebo (N=975) Prozac (N=266) Placebo (N=89) Prozac (N=450) Placebo (N=267) Prozac (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence2 2 -- -- -- 7 -- 1 -- Abnormal ejaculation2 -- -- 7 -- 7 -- 2 1 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US 942 data for panic disorder clinical trials. 943 2 Denominator used was for males only (N=690 Prozac major depressive disorder; N=410 placebo major 944 depressive disorder; N=116 Prozac OCD; N=43 placebo OCD; N=14 Prozac bulimia; N=1 placebo bulimia; 945 N=162 Prozac panic; N=121 placebo panic). 946 -- Incidence less than 1%. 947 948 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Table 3: Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, 949 OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 950 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Event2 Prozac (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US 951 data for panic disorder clinical trials. 952 2 Included are events reported by at least 2% of patients taking Prozac, except the following events, which had an 953 incidence on placebo ≥ Prozac (major depressive disorder, OCD, bulimia, and panic disorder combined): 954 abdominal pain, abnormal dreams, accidental injury, back pain, cough increased, major depressive disorder 955 (includes suicidal thoughts), dysmenorrhea, infection, myalgia, pain, paresthesia, pharyngitis, rhinitis, sinusitis. 956 -- Incidence less than 1%. 957 958 Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic 959 disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 4 960 lists the adverse events associated with discontinuation of Prozac treatment (incidence at least 961 twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event 962 associated with discontinuation) in major depressive disorder, OCD, bulimia, and panic disorder 963 clinical trials, plus non-US panic disorder clinical trials. 964 965 Table 4: Most Common Adverse Events Associated with Discontinuation in Major 966 Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical 967 Trials1 968 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) -- -- Rash (1%) -- -- 1 Includes US major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic 969 disorder clinical trials. 970 971 Other adverse events in pediatric patients (children and adolescents) — Treatment-emergent 972 adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142 973 placebo-treated). The overall profile of adverse events was generally similar to that seen in adult 974 studies, as shown in Tables 2 and 3. However, the following adverse events (excluding those 975 which appear in the body or footnotes of Tables 2 and 3 and those for which the COSTART 976 terms were uninformative or misleading) were reported at an incidence of at least 2% for 977 fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, 978 epistaxis, urinary frequency, and menorrhagia. 979 The most common adverse event (incidence at least 1% for fluoxetine and greater than 980 placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 981 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for 982 fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary event 983 associated with discontinuation was collected. 984 Events observed in Prozac Weekly clinical trials — Treatment-emergent adverse events in 985 clinical trials with Prozac Weekly were similar to the adverse events reported by patients in 986 clinical trials with Prozac daily. In a placebo-controlled clinical trial, more patients taking Prozac 987 Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking 988 Prozac 20 mg daily (10% versus 5%, respectively). 989 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual 990 performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they 991 may also be a consequence of pharmacologic treatment. In particular, some evidence suggests 992 that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and 993 severity of untoward experiences involving sexual desire, performance, and satisfaction are 994 difficult to obtain, however, in part because patients and physicians may be reluctant to discuss 995 them. Accordingly, estimates of the incidence of untoward sexual experience and performance, 996 cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in 997 US major depressive disorder, OCD, and bulimia placebo-controlled clinical trials, decreased 998 libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% 999 fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of 1000 orgasmic dysfunction, including anorgasmia. 1001 There are no adequate and well-controlled studies examining sexual dysfunction with 1002 fluoxetine treatment. 1003 Priapism has been reported with all SSRIs. 1004 While it is difficult to know the precise risk of sexual dysfunction associated with the use of 1005 SSRIs, physicians should routinely inquire about such possible side effects. 1006 Other Events Observed in Clinical Trials 1007 Following is a list of all treatment-emergent adverse events reported at anytime by individuals 1008 taking fluoxetine in US clinical trials as of May 8, 1995 (10,782 patients) except (1) those listed 1009 in the body or footnotes of Tables 2 or 3 above or elsewhere in labeling; (2) those for which the 1010 COSTART terms were uninformative or misleading; (3) those events for which a causal 1011 relationship to Prozac use was considered remote; and (4) events occurring in only 1 patient 1012 treated with Prozac and which did not have a substantial probability of being acutely 1013 life-threatening. 1014 Events are classified within body system categories using the following definitions: frequent 1015 adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; 1016 infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those 1017 occurring in less than 1/1000 patients. 1018 Body as a Whole — Frequent: chest pain, chills; Infrequent: chills and fever, face edema, 1019 intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, 1020 hypothermia, intentional injury, neuroleptic malignant syndrome1, photosensitivity reaction. 1021 Cardiovascular System — Frequent: hemorrhage, hypertension, palpitation; Infrequent: 1022 angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, 1023 postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, 1024 bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart 1025 arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, 1026 thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. 1027 Digestive System — Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous 1028 stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, 1029 glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, 1030 melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: 1031 biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal 1032 incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, 1033 intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary 1034 gland enlargement, stomach ulcer hemorrhage, tongue edema. 1035 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Endocrine System — Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. 1036 Hemic and Lymphatic System — Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, 1037 hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, 1038 thrombocythemia, thrombocytopenia. 1039 Metabolic and Nutritional — Frequent: weight gain; Infrequent: dehydration, generalized 1040 edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol 1041 intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, 1042 hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. 1043 Musculoskeletal System — Infrequent: arthritis, bone pain, bursitis, leg cramps, 1044 tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, 1045 osteomyelitis, osteoporosis, rheumatoid arthritis. 1046 Nervous System — Frequent: agitation, amnesia, confusion, emotional lability, sleep 1047 disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal 1048 syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, 1049 hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, 1050 neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder2, psychosis, vertigo; 1051 Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, 1052 delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, 1053 paralysis, reflexes decreased, reflexes increased, stupor. 1054 Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, 1055 atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, 1056 lung edema, pneumothorax, stridor. 1057 Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, eczema, 1058 maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, 1059 herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. 1060 Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry 1061 eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye 1062 hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field 1063 defect. 1064 Urogenital System — Frequent: urinary frequency; Infrequent: abortion3, albuminuria, 1065 amenorrhea3, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation3, 1066 fibrocystic breast3, hematuria, leukorrhea3, menorrhagia3, metrorrhagia3, nocturia, polyuria, 1067 urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage3; Rare: breast 1068 engorgement, glycosuria, hypomenorrhea3, kidney pain, oliguria, priapism3, uterine 1069 hemorrhage3, uterine fibroids enlarged3. 1070 1 Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome. 1071 2 Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. 1072 3 Adjusted for gender. 1073 1074 Postintroduction Reports 1075 Voluntary reports of adverse events temporally associated with Prozac that have been received 1076 since market introduction and that may have no causal relationship with the drug include the 1077 following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic 1078 jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory 1079 syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 1080 weeks of fluoxetine therapy and which completely resolved over the next few months following 1081 drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, 1082 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, 1083 hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, 1084 misuse/abuse, movement disorders developing in patients with risk factors including drugs 1085 associated with such events and worsening of preexisting movement disorders, neuroleptic 1086 malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary 1087 embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and 1088 symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), 1089 Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, 1090 thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia 1091 (including torsades de pointes-type arrhythmias), and violent behaviors. 1092 DRUG ABUSE AND DEPENDENCE 1093 Controlled substance class — Prozac is not a controlled substance. 1094 Physical and psychological dependence — Prozac has not been systematically studied, in 1095 animals or humans, for its potential for abuse, tolerance, or physical dependence. While the 1096 premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal 1097 syndrome or any drug seeking behavior, these observations were not systematic and it is not 1098 possible to predict on the basis of this limited experience the extent to which a CNS active drug 1099 will be misused, diverted, and/or abused once marketed. Consequently, physicians should 1100 carefully evaluate patients for history of drug abuse and follow such patients closely, observing 1101 them for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation of 1102 dose, drug-seeking behavior). 1103 OVERDOSAGE 1104 Human Experience 1105 Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients 1106 (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with 1107 other drugs, reported from this population, there were 195 deaths. 1108 Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a 1109 fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, 1110 including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, 1111 pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, 1112 and hypomania. The remaining 206 patients had an unknown outcome. The most common signs 1113 and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, 1114 tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult 1115 patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. 1116 However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been 1117 associated with lethal outcome, but causality has not been established. 1118 Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose 1119 involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients 1120 completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown 1121 outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s 1122 syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 1123 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and 1124 promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in 1125 children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which 1126 was nonlethal. 1127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 Other important adverse events reported with fluoxetine overdose (single or multiple drugs) 1128 include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular 1129 tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic 1130 malignant syndrome-like events, pyrexia, stupor, and syncope. 1131 Animal Experience 1132 Studies in animals do not provide precise or necessarily valid information about the treatment 1133 of human overdose. However, animal experiments can provide useful insights into possible 1134 treatment strategies. 1135 The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. 1136 Acute high oral doses produced hyperirritability and convulsions in several animal species. 1137 Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. 1138 Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary 1139 dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure 1140 occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, 1141 chronically. 1142 In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation 1143 of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. 1144 Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the 1145 ECG should ordinarily be monitored in cases of human overdose (see Management of 1146 Overdose). 1147 Management of Overdose 1148 Treatment should consist of those general measures employed in the management of 1149 overdosage with any drug effective in the treatment of major depressive disorder. 1150 Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital 1151 signs. General supportive and symptomatic measures are also recommended. Induction of emesis 1152 is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway 1153 protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic 1154 patients. 1155 Activated charcoal should be administered. Due to the large volume of distribution of this 1156 drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of 1157 benefit. No specific antidotes for fluoxetine are known. 1158 A specific caution involves patients who are taking or have recently taken fluoxetine and might 1159 ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or 1160 an active metabolite may increase the possibility of clinically significant sequelae and extend the 1161 time needed for close medical observation (see Other drugs effective in the treatment of major 1162 depressive disorder under PRECAUTIONS). 1163 Based on experience in animals, which may not be relevant to humans, fluoxetine-induced 1164 seizures that fail to remit spontaneously may respond to diazepam. 1165 In managing overdosage, consider the possibility of multiple drug involvement. The physician 1166 should consider contacting a poison control center for additional information on the treatment of 1167 any overdose. Telephone numbers for certified poison control centers are listed in the 1168 Physicians’ Desk Reference (PDR). 1169 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 DOSAGE AND ADMINISTRATION 1170 Major Depressive Disorder 1171 Initial Treatment 1172 Adult — In controlled trials used to support the efficacy of fluoxetine, patients were 1173 administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, 1174 and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response 1175 in major depressive disorder in most cases. Consequently, a dose of 20 mg/day, administered in 1176 the morning, is recommended as the initial dose. 1177 A dose increase may be considered after several weeks if insufficient clinical improvement is 1178 observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID 1179 schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. 1180 Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials 1181 of fluoxetine supporting its effectiveness in the treatment of major depressive disorder, patients 1182 were administered fluoxetine doses of 10 to 20 mg/day (see CLINICAL TRIALS). Treatment 1183 should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should 1184 be increased to 20 mg/day. 1185 However, due to higher plasma levels in lower weight children, the starting and target dose in 1186 this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several 1187 weeks if insufficient clinical improvement is observed. 1188 All patients — As with other drugs effective in the treatment of major depressive disorder, the 1189 full effect may be delayed until 4 weeks of treatment or longer. 1190 As with many other medications, a lower or less frequent dosage should be used in patients 1191 with hepatic impairment. A lower or less frequent dosage should also be considered for the 1192 elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or 1193 on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely 1194 necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use 1195 in Patients with Concomitant Illness under PRECAUTIONS). 1196 Maintenance/Continuation/Extended Treatment 1197 It is generally agreed that acute episodes of major depressive disorder require several months 1198 or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is 1199 identical to the dose needed to maintain and/or sustain euthymia is unknown. 1200 Daily Dosing 1201 Systematic evaluation of Prozac in adult patients has shown that its efficacy in major 1202 depressive disorder is maintained for periods of up to 38 weeks following 12 weeks of 1203 open-label acute treatment (50 weeks total) at a dose of 20 mg/day (see CLINICAL TRIALS). 1204 Weekly Dosing 1205 Systematic evaluation of Prozac Weekly in adult patients has shown that its efficacy in major 1206 depressive disorder is maintained for periods of up to 25 weeks with once-weekly dosing 1207 following 13 weeks of open-label treatment with Prozac 20 mg once daily. However, therapeutic 1208 equivalence of Prozac Weekly given on a once-weekly basis with Prozac 20 mg given daily for 1209 delaying time to relapse has not been established (see CLINICAL TRIALS). 1210 Weekly dosing with Prozac Weekly capsules is recommended to be initiated 7 days after the 1211 last daily dose of Prozac 20 mg (see Weekly dosing under CLINICAL PHARMACOLOGY). 1212 If satisfactory response is not maintained with Prozac Weekly, consider reestablishing a daily 1213 dosing regimen (see CLINICAL TRIALS). 1214 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 Switching Patients to a Tricyclic Antidepressant (TCA) 1215 Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be 1216 monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see 1217 Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS, Drug 1218 Interactions). 1219 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) 1220 At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy 1221 with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping 1222 Prozac before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS). 1223 Obsessive Compulsive Disorder 1224 Initial Treatment 1225 Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the 1226 treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine 1227 or placebo (see CLINICAL TRIALS). In 1 of these studies, no dose-response relationship for 1228 effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the 1229 morning, is recommended as the initial dose. Since there was a suggestion of a possible 1230 dose-response relationship for effectiveness in the second study, a dose increase may be 1231 considered after several weeks if insufficient clinical improvement is observed. The full 1232 therapeutic effect may be delayed until 5 weeks of treatment or longer. 1233 Doses above 20 mg/day may be administered on a once-a-day (i.e., morning) or BID schedule 1234 (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of 1235 up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose 1236 should not exceed 80 mg/day. 1237 Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting 1238 its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the 1239 range of 10 to 60 mg/day (see CLINICAL TRIALS). 1240 In adolescents and higher weight children, treatment should be initiated with a dose of 1241 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases 1242 may be considered after several more weeks if insufficient clinical improvement is observed. A 1243 dose range of 20 to 60 mg/day is recommended. 1244 In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional 1245 dose increases may be considered after several more weeks if insufficient clinical improvement 1246 is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses 1247 greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. 1248 All patients — As with the use of Prozac in the treatment of major depressive disorder, a lower 1249 or less frequent dosage should be used in patients with hepatic impairment. A lower or less 1250 frequent dosage should also be considered for the elderly (see Geriatric Use under 1251 PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant 1252 medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver 1253 disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with 1254 Concomitant Illness under PRECAUTIONS). 1255 Maintenance/Continuation Treatment 1256 While there are no systematic studies that answer the question of how long to continue Prozac, 1257 OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. 1258 Although the efficacy of Prozac after 13 weeks has not been documented in controlled trials, 1259 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 adult patients have been continued in therapy under double-blind conditions for up to an 1260 additional 6 months without loss of benefit. However, dosage adjustments should be made to 1261 maintain the patient on the lowest effective dosage, and patients should be periodically 1262 reassessed to determine the need for treatment. 1263 Bulimia Nervosa 1264 Initial Treatment 1265 In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of 1266 bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or 1267 placebo (see CLINICAL TRIALS). Only the 60-mg dose was statistically significantly superior 1268 to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the 1269 recommended dose is 60 mg/day, administered in the morning. For some patients it may be 1270 advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day 1271 have not been systematically studied in patients with bulimia. 1272 As with the use of Prozac in the treatment of major depressive disorder and OCD, a lower or 1273 less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent 1274 dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and 1275 for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments 1276 for renal impairment are not routinely necessary (see Liver disease and Renal disease under 1277 CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under 1278 PRECAUTIONS). 1279 Maintenance/Continuation Treatment 1280 Systematic evaluation of continuing Prozac 60 mg/day for periods of up to 52 weeks in 1281 patients with bulimia who have responded while taking Prozac 60 mg/day during an 8-week 1282 acute treatment phase has demonstrated a benefit of such maintenance treatment (see CLINICAL 1283 TRIALS). Nevertheless, patients should be periodically reassessed to determine the need for 1284 maintenance treatment. 1285 Panic Disorder 1286 Initial Treatment 1287 In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of 1288 panic disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see 1289 CLINICAL TRIALS). Treatment should be initiated with a dose of 10 mg/day. After 1 week, the 1290 dose should be increased to 20 mg/day. The most frequently administered dose in the 2 1291 flexible-dose clinical trials was 20 mg/day. 1292 A dose increase may be considered after several weeks if no clinical improvement is observed. 1293 Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with panic 1294 disorder. 1295 As with the use of Prozac in other indications, a lower or less frequent dosage should be used 1296 in patients with hepatic impairment. A lower or less frequent dosage should also be considered 1297 for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent 1298 disease or on multiple concomitant medications. Dosage adjustments for renal impairment are 1299 not routinely necessary (see Liver disease and Renal disease under CLINICAL 1300 PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). 1301 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 Maintenance/Continuation Treatment 1302 While there are no systematic studies that answer the question of how long to continue Prozac, 1303 panic disorder is a chronic condition and it is reasonable to consider continuation for a 1304 responding patient. Nevertheless, patients should be periodically reassessed to determine the 1305 need for continued treatment. 1306 Special Populations 1307 Treatment of Pregnant Women During the Third Trimester 1308 Neonates exposed to Prozac and other SSRIs or SNRIs, late in the third trimester have 1309 developed complications requiring prolonged hospitalization, respiratory support, and tube 1310 feeding (see PRECAUTIONS). When treating pregnant women with Prozac during the third 1311 trimester, the physician should carefully consider the potential risks and benefits of treatment. 1312 The physician may consider tapering Prozac in the third trimester. 1313 Discontinuation of Treatment with Prozac 1314 Symptoms associated with discontinuation of Prozac and other SSRIs and SNRIs, have been 1315 reported (see PRECAUTIONS). Patients should be monitored for these symptoms when 1316 discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is 1317 recommended whenever possible. If intolerable symptoms occur following a decrease in the dose 1318 or upon discontinuation of treatment, then resuming the previously prescribed dose may be 1319 considered. Subsequently, the physician may continue decreasing the dose but at a more gradual 1320 rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of 1321 therapy which may minimize the risk of discontinuation symptoms with this drug. 1322 HOW SUPPLIED 1323 The following products are manufactured by Eli Lilly and Company for Dista Products 1324 Company. 1325 1326 Prozac® Pulvules®, USP, are available in: The 10-mg1, Pulvule is opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body: NDC 0777-3104-02 (PU31042) - Bottles of 100 The 20-mg1 Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body: NDC 0777-3105-30 (PU31052) - Bottles of 30 NDC 0777-3105-02 (PU31052) - Bottles of 100 NDC 0777-3105-07 (PU31052) - Bottles of 2000 The 40-mg1 Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body: NDC 0777-3107-30 (PU31072) - Bottles of 30 The following is manufactured by OSG Norwich Pharmaceuticals, Inc., North Norwich, NY, 13814, for Dista Products Company: Liquid, Oral Solution is available in: 20 mg1 per 5 mL with mint flavor: NDC 0777-5120-58 (MS-51203) - Bottles of 120 mL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 The following product is manufactured and distributed by Eli Lilly and Company: Prozac® Weekly™ Capsules are available in: The 90-mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) - Blister package of 4 ______________________ 1327 1 Fluoxetine base equivalent. 1328 2 Protect from light. 1329 3 Dispense in a tight, light-resistant container. 1330 1331 Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). 1332 ANIMAL TOXICOLOGY 1333 Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine 1334 chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid 1335 accumulation in animals has been observed with many cationic amphiphilic drugs, including 1336 fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. 1337 Literature revised January 16, 2008 1338 Eli Lilly and Company 1339 Indianapolis, IN 46285, USA 1340 1341 www.lilly.com 1342 PV 5326 DPP PRINTED IN USA 1343 Medication Guide 1344 Antidepressant Medicines, Depression and other Serious Mental 1345 Illnesses, and Suicidal Thoughts or Actions 1346 Read the Medication Guide that comes with your or your family member’s antidepressant 1347 medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with 1348 antidepressant medicines. Talk to your, or your family member’s, healthcare provider 1349 about: 1350 • all risks and benefits of treatment with antidepressant medicines 1351 • all treatment choices for depression or other serious mental illness 1352 What is the most important information I should know about antidepressant 1353 medicines, depression and other serious mental illnesses, and suicidal thoughts 1354 or actions? 1355 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, 1356 teenagers, and young adults within the first few months of treatment. 1357 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 2. Depression and other serious mental illnesses are the most important causes of 1358 suicidal thoughts and actions. Some people may have a particularly high risk of 1359 having suicidal thoughts or actions. These include people who have (or have a family 1360 history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or 1361 actions. 1362 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a 1363 family member? 1364 • Pay close attention to any changes, especially sudden changes, in mood, behaviors, 1365 thoughts, or feelings. This is very important when an antidepressant medicine is 1366 started or when the dose is changed. 1367 • Call the healthcare provider right away to report new or sudden changes in mood, 1368 behavior, thoughts, or feelings. 1369 • Keep all follow-up visits with the healthcare provider as scheduled. Call the 1370 healthcare provider between visits as needed, especially if you have concerns about 1371 symptoms. 1372 Call a healthcare provider right away if you or your family member has any of the 1373 following symptoms, especially if they are new, worse, or worry you: 1374 • thoughts about suicide or dying 1375 • attempts to commit suicide 1376 • new or worse depression 1377 • new or worse anxiety 1378 • feeling very agitated or restless 1379 • panic attacks 1380 • trouble sleeping (insomnia) 1381 • new or worse irritability 1382 • acting aggressive, being angry, or violent 1383 • acting on dangerous impulses 1384 • an extreme increase in activity and talking (mania) 1385 • other unusual changes in behavior or mood 1386 What else do I need to know about antidepressant medicines? 1387 • Never stop an antidepressant medicine without first talking to a healthcare provider. 1388 Stopping an antidepressant medicine suddenly can cause other symptoms. 1389 • Antidepressants are medicines used to treat depression and other illnesses. It is 1390 important to discuss all the risks of treating depression and also the risks of not treating it. 1391 Patients and their families or other caregivers should discuss all treatment choices with the 1392 healthcare provider, not just the use of antidepressants. 1393 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 • Antidepressant medicines have other side effects. Talk to the healthcare provider about 1394 the side effects of the medicine prescribed for you or your family member. 1395 • Antidepressant medicines can interact with other medicines. Know all of the medicines 1396 that you or your family member takes. Keep a list of all medicines to show the healthcare 1397 provider. Do not start new medicines without first checking with your healthcare provider. 1398 • Not all antidepressant medicines prescribed for children are FDA approved for use in 1399 children. Talk to your child’s healthcare provider for more information. 1400 This Medication Guide has been approved by the US Food and Drug Administration for 1401 all antidepressants. 1402 Patient Information revised June 21, 2007 1403 PV 5083 AMP 1404 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:04.734519	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018936s084,020101s039,021235s011lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 84}
11,376	1 PV 5971 UCP SARAFEM® fluoxetine hydrochloride WARNING 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 SARAFEM 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. SARAFEM is not approved for use in pediatric patients with MDD and obsessive compulsive disorder (OCD). (See WARNINGS, PRECAUTIONS, Information for Patients, and PRECAUTIONS, Pediatric Use.) DESCRIPTION SARAFEM® (fluoxetine hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral administration; fluoxetine was initially developed and marketed as an antidepressant (Prozac®, fluoxetine capsules, USP). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: Chemical Structure Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol) or 20 mg (64.7 μmol) of fluoxetine. The Pulvules also contain dimethicone, FD&C Blue No. 1, FD&C Red No. 3, FD&C Yellow No. 6, gelatin, sodium lauryl sulfate, starch, and titanium dioxide. CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of action of fluoxetine in premenstrual dysphoric disorder (PMDD) is unknown, but is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in humans have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of certain psychoactive drugs. Fluoxetine has little affinity for these receptors. Absorption, Distribution, Metabolism, and Excretion Systemic bioavailability — In humans, following a single oral 40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequentially. Thus, fluoxetine may be administered with or without food. Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS). Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical issues related to metabolism/elimination — The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine’s clinical use. Variability in metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see Drug Interactions under PRECAUTIONS). Accumulation and slow elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of SARAFEM. Liver disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see Use in Patients with Concomitant Illness under PRECAUTIONS and DOSAGE AND ADMINISTRATION). Renal disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (see Use in Patients with Concomitant Illness under PRECAUTIONS and DOSAGE AND ADMINISTRATION). CLINICAL TRIALS Premenstrual Dysphoric Disorder (PMDD) The effectiveness of SARAFEM for the treatment of PMDD was established in 3 placebo-controlled trials (1 intermittent and 2 continuous dosing). In an intermittent dosing trial described below, patients met Diagnostic and Statistical Manual-4th edition (DSM-IV) criteria for PMDD. In the continuous dosing trials described below, patients met Diagnostic and Statistical Manual-3rd edition revised (DSM-IIIR) criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as PMDD in the DSM-IV. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of fluoxetine in combination with oral contraceptives for the treatment of PMDD is unknown. In an intermittent dosing double-blind, parallel group study of 3 months duration, patients (N=260 randomized) were treated with fluoxetine 10 mg/day, fluoxetine 20 mg/day, or placebo. Fluoxetine or placebo was started 14 days prior to the anticipated onset of menstruation and was continued through the first full day of menses. Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. Fluoxetine 20 mg/day was shown to be significantly more effective than This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 placebo as measured by the DRSP total score. Fluoxetine 10 mg/day was not shown to be significantly more effective than placebo on this outcome. The average DRSP total score decreased 38% on fluoxetine 20 mg/day, 35% on fluoxetine 10 mg/day, and 30% on placebo. In the first continuous dosing double-blind, parallel group study of 6 months duration involving N=320 patients, fixed doses of fluoxetine 20 and 60 mg/day given daily throughout the menstrual cycle were shown to be significantly more effective than placebo as measured by a Visual Analogue Scale (VAS) total score (including mood and physical symptoms). The average total VAS score decreased 7% on placebo treatment, 36% on 20 mg, and 39% on 60 mg fluoxetine. The difference between the 20- and 60-mg doses was not statistically significant. The following table shows the percentage of patients meeting criteria for either moderate or marked improvement on the VAS total score: Percentage of Patients Moderately and Markedly Improved (>50% and 75% reduction, respectively, from baseline Luteal Phase VAS total score) Improvement N Placebo N Fluoxetine 20 mg N Fluoxetine 60 mg Moderate 94 11% 95 37% 85 38% Marked 94 4% 95 6% 85 18% In a second continuous dosing double-blind, cross-over study, patients (N=19) were treated with fluoxetine 20 to 60 mg/day (mean dose = 27 mg/day) and placebo daily throughout the menstrual cycle for a period of 3 months each. Fluoxetine was significantly more effective than placebo as measured by within cycle follicular to luteal phase changes in the VAS total score (mood, physical, and social impairment symptoms). The average VAS total score (follicular to luteal phase increase) was 3.8 times higher during placebo treatment than what was observed during fluoxetine treatment. In another continuous dosing double-blind, parallel group study, patients with LLPDD (N=42) were treated daily with fluoxetine 20 mg/day, bupropion 300 mg/day, or placebo for 2 months. Neither fluoxetine nor bupropion was shown to be superior to placebo on the primary endpoint, i.e., response rate [defined as a rating of 1 (very much improved) or 2 (much improved) on the CGI], possibly due to sample size. INDICATIONS AND USAGE SARAFEM is indicated for the treatment of premenstrual dysphoric disorder (PMDD). The efficacy of fluoxetine in the treatment of PMDD was established in 3 placebo-controlled trials (see CLINICAL TRIALS). The essential features of PMDD, according to the DSM-IV, include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant. The effectiveness of SARAFEM in long-term use, that is, for more than 6 months, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 SARAFEM for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS SARAFEM is contraindicated in patients known to be hypersensitive to it. Monoamine oxidase inhibitors — There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY)] should be allowed after stopping fluoxetine before starting an MAOI. Pimozide — Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS). Thioridazine — Thioridazine should not be administered with SARAFEM or within a minimum of 5 weeks after SARAFEM has been discontinued (see WARNINGS). 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 versus 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 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. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with SARAFEM, for a description of the risks of discontinuation of SARAFEM). 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 SARAFEM should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 It should be noted that SARAFEM is not approved for use in treating any indications in the pediatric population. 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 SARAFEM is not approved for use in treating bipolar depression. Rash and Possibly Allergic Events — In 4 clinical trials for PMDD, 4% of 415 patients treated with SARAFEM reported rash and/or urticaria. None of these cases were classified as serious and 2 of 415 patients (both receiving 60 mg) were withdrawn from treatment because of rash and/or urticaria. In US fluoxetine clinical trials for conditions other than PMDD, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely. In premarketing clinical trials of fluoxetine for conditions other than PMDD, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of fluoxetine for other indications, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, SARAFEM should be discontinued. Serotonin Syndrome — The development of a potentially life-threatening serotonin syndrome may occur with SNRIs and SSRIs, including SARAFEM treatment, particularly with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of SARAFEM with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and Drug Interactions under PRECAUTIONS). If concomitant treatment of SARAFEM with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Drug Interactions under PRECAUTIONS). The concomitant use of SARAFEM with serotonin precursors (such as tryptophan) is not recommended (see Drug Interactions under PRECAUTIONS). Potential Interaction with Thioridazine — In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS). Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS). PRECAUTIONS General Abnormal Bleeding — Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of SARAFEM with NSAIDs, aspirin, or other drugs that affect coagulation. Anxiety and Insomnia — In 2 placebo-controlled trials of fluoxetine in PMDD, treatment-emergent adverse events were assessed. Rates were as follows for SARAFEM 20 mg (the recommended dose) continuous and intermittent pooled, SARAFEM 60 mg continuous, and pooled placebo, respectively: anxiety (3%, 9%, and 4%); nervousness (5%, 9%, and 3%); and insomnia (9%, 26%, and 7%). For individual rates for SARAFEM 20 mg given as continuous and intermittent dosing, see Table 2 and accompanying footnote under ADVERSE REACTIONS. Events associated with discontinuation for SARAFEM 20 mg continuous and intermittent pooled, SARAFEM 60 mg continuous, and pooled placebo, respectively, were: anxiety (0%, 6%, and 1%); nervousness (1%, 0%, and 0.5%); and insomnia (1%, 4%, and 0.5%). In US placebo-controlled clinical trials of fluoxetine for other approved indications, anxiety, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 nervousness, and insomnia have been among the most commonly reported adverse events (see Table 3 under ADVERSE REACTIONS). Altered Appetite and Weight — In 2 placebo-controlled trials of fluoxetine in PMDD, rates for anorexia were as follows for SARAFEM 20 mg (the recommended dose) continuous and intermittent pooled, SARAFEM 60 mg continuous, and pooled placebo, respectively: 4%, 13%, and 2%. For individual rates for SARAFEM 20 mg continuous and intermittent, see footnote accompanying Table 2 under ADVERSE REACTIONS. In 2 placebo-controlled trials (only one of which included a dose of 60 mg/day), potentially clinically significant weight gain (≥7%) occurred in 8% of patients on SARAFEM 20 mg, 6% of patients on SARAFEM 60 mg, and 1% of patients on placebo. Potentially clinically significant weight loss (≥7%) occurred in 7% of patients on SARAFEM 20 mg, 12% of patients on SARAFEM 60 mg, and 3% of patients on placebo. In US placebo-controlled clinical trials of fluoxetine for other approved indications, changes in appetite and weight have also been reported (see Table 3 and Other events observed in US clinical trials under ADVERSE REACTIONS). Activation of Mania/Hypomania — No patients treated with SARAFEM in 4 PMDD clinical trials (N=415) reported mania/hypomania. In all US fluoxetine clinical trials for conditions other than PMDD, 0.7% of 10,782 patients reported mania/hypomania. Activation of mania/hypomania may occur with medications used to treat depression, especially in patients predisposed to Bipolar Affective Disorder. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when SARAFEM was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. Seizures — No patients treated with SARAFEM in 4 PMDD clinical trials (N=415) reported seizures. In all US fluoxetine clinical trials for conditions other than PMDD, 0.2% of 10,782 patients reported seizures. Antidepressant medication should be introduced with care in patients with a history of seizures. The Long Elimination Half-Lives of Fluoxetine and its Metabolites — Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Use in Patients with Concomitant Illness — Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials for a condition other than PMDD were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances (see Liver disease under CLINICAL PHARMACOLOGY). A lower or less frequent dose should be used in patients with cirrhosis (see DOSAGE AND ADMINISTRATION). Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma (see Renal disease under CLINICAL PHARMACOLOGY). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE AND ADMINISTRATION). In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued. Discontinuation of Treatment with SARAFEM — During marketing of SARAFEM and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with SARAFEM. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see DOSAGE AND ADMINISTRATION). Interference with Cognitive and Motor Performance — Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. 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 SARAFEM and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for SARAFEM. 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 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 SARAFEM. Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding. 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. Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SARAFEM and triptans, tramadol or other serotonergic agents. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see CONTRAINDICATIONS and WARNINGS). Drugs metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. CNS active drugs — The risk of using fluoxetine in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between serotonin specific reuptake inhibitors (SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and fluoxetine. Concomitant use of fluoxetine and pimozide is contraindicated (see CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS and WARNINGS. Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. Tryptophan — Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. Monoamine oxidase inhibitors — See CONTRAINDICATIONS. Antidepressants — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY, and Drugs metabolized by CYP2D6 under Drug Interactions). Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including SARAFEM, and the potential for serotonin syndrome, caution is advised when SARAFEM is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see Serotonin Syndrome under WARNINGS). The concomitant use of SARAFEM with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of SARAFEM with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Serotonin Syndrome under WARNINGS). Potential effects of coadministration of drugs tightly bound to plasma proteins — Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs that interfere with hemostasis (NSAIDs, aspirin, warfarin, etc.) — Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluoxetine. Warfarin — Altered anticoagulant effects, including increased bleeding, have been reported when fluoxetine is coadministered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped. Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. Carcinogenesis, Mutagenesis, Impairment of Fertility There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) was not observed. Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity. Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use). Pregnancy Pregnancy Category C — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m2 basis), throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects — Neonates exposed to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Monoamine oxidase inhibitors under CONTRAINDICATIONS). Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. Labor and Delivery The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 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 SARAFEM in a child or adolescent must balance the potential risks with the clinical need. Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis. In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain. Geriatric Use The diagnosis of PMDD is not applicable to postmenopausal women. ADVERSE REACTIONS In 1 of 3 placebo-controlled, continuous-dosing trials and 1 placebo-controlled, intermittent-dosing trial of fluoxetine in PMDD, treatment-emergent adverse events reporting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 rates were assessed. The information from Table 2 included under ADVERSE REACTIONS is based on data from the continuous-dosing trial at the recommended dose of SARAFEM (SARAFEM 20 mg, N=104; placebo, N=108) and data from the intermittent-dosing trial of fluoxetine in PMDD (SARAFEM 20 mg, N=86; placebo, N=88). In addition, a broader set of information on treatment-emergent adverse events in the population of female patients, 18 to 45 years of age from the US placebo-controlled depression, OCD, and bulimia clinical trials, is presented for comparison (see Table 3). Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in placebo-controlled PMDD clinical trials — Table 2 enumerates the most common treatment-emergent adverse events associated with the use of SARAFEM 20 mg (incidence of at least 5% for SARAFEM 20 mg and greater than placebo) for the treatment of PMDD. Table 2: Most Common Treatment-Emergent Adverse Events: Incidence in PMDD Placebo-Controlled Clinical Trials Percentage of Patients Reporting Event Body System/Adverse Event1 SARAFEM 20 mg/day Continuously (N=104) SARAFEM 20 mg/day Intermittently (N=86) Placebo (Pooled) (N=196) Body as a Whole Headache 13 15 11 Asthenia 12 8 4 Pain 9 3 7 Accidental injury 8 1 5 Infection 7 0 3 Flu syndrome 12 3 7 Digestive System Nausea 13 9 6 Diarrhea 6 2 6 Nervous System This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Insomnia 9 10 7 Dizziness 7 2 3 Nervousness 7 3 3 Thinking abnormal2 6 5 0 Libido decreased 3 9 1 Respiratory System Rhinitis 23 16 15 Pharyngitis 10 6 5 1 Included in the table are events reported by at least 5% of patients taking SARAFEM 20 mg either continuously or intermittently. For additional adverse event terms referenced in PRECAUTIONS, reporting rates for SARAFEM 20 mg continuous and intermittent were, respectively: anxiety 4.8%, 1.2% and anorexia 3.8%, 3.5%. 2 Thinking abnormal is the COSTART term that captures concentration difficulties. Incidence in US depression, OCD, and bulimia placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse events associated with the use of fluoxetine up to 80 mg (incidence of at least 2% for fluoxetine and greater than placebo) in female patients ages 18 to 45 years from US placebo-controlled clinical trials in the treatment of depression, OCD, and bulimia. Table 3: Treatment-Emergent Adverse Events: Incidence in Female Patients Ages 18 to 45 Years in US Depression, OCD, and Bulimia Placebo-Controlled Clinical Trials Percentage of Patients Reporting Event Body System/Adverse Event1 Fluoxetine (N=1145) Placebo (N=553) Body as a Whole Headache 24 21 Asthenia 14 6 Flu syndrome 7 3 Abdominal pain 6 5 Accidental injury 4 3 Fever 3 2 Cardiovascular System Palpitation 3 2 Vasodilatation 3 1 Digestive System Nausea 27 11 Anorexia 11 4 Dry mouth 11 8 Diarrhea 10 7 Dyspepsia 7 5 Constipation 5 3 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 3 1 Nervous System Insomnia 24 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Nervousness 14 10 Anxiety 13 9 Somnolence 13 6 Tremor 12 1 Dizziness 11 5 Libido decreased 4 1 Abnormal dreams 3 2 Thinking abnormal2 3 2 Respiratory System Pharyngitis 6 5 Yawn 5 -- Skin and Appendages Sweating 8 3 Rash 5 3 Special Senses Abnormal vision 3 1 Urogenital System Urinary frequency 2 1 1 Included are events reported by at least 2% of patients taking fluoxetine, except the following events, which had an incidence on placebo > fluoxetine (depression, OCD, and bulimia combined): back pain, cough increased, depression (includes suicidal thoughts), dysmenorrhea, flatulence, infection, myalgia, pain, pruritus, rhinitis, sinusitis. 2 Thinking abnormal is the COSTART term that captures concentration difficulties. -- Incidence less than 0.5%. Associated with discontinuation in two placebo-controlled PMDD clinical trials — In a continuous-dosing PMDD placebo-controlled trial, the most common adverse event (incidence at least 2% for SARAFEM 20 mg and greater than placebo) associated with discontinuation was nausea (3% for SARAFEM 20 mg, N=104 and 1% for placebo, N=108). In an intermittent-dosing placebo-controlled trial, no events associated with discontinuation reached an incidence of 2% for SARAFEM 20 mg. In these clinical trials, more than one event may have been recorded as the cause of discontinuation. Associated with discontinuation in US depression, OCD, and bulimia placebo-controlled clinical trials (excluding data from extensions of trials) — In female patients age 18 to 45 years in US depression, OCD, and bulimia placebo-controlled clinical trials combined, which collected a single primary event associated with discontinuation (incidence at least 1% for fluoxetine and at least twice that for placebo), insomnia (1%, N=561) was the only event reported. Female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a mood-related disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. For example, in women (age 18 to 45) receiving fluoxetine for indications other than PMDD, decreased libido was seen at an incidence of 4% for fluoxetine compared with 1% for placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 There have been spontaneous reports in women (age 18 to 45) taking fluoxetine for indications other than PMDD of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Other Events Observed in US Clinical Trials Following is a list of all treatment-emergent adverse events reported at anytime by females and males taking fluoxetine in all US clinical trials for conditions other than PMDD as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 2 or 3 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to fluoxetine use was considered remote; (4) events occurring in only 1 patient treated with fluoxetine and which did not have a substantial probability of being acutely life-threatening; and (5) events that could only occur in males. Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients. Body as a Whole — Frequent: chest pain and chills; Infrequent: chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome, photosensitivity reaction. Cardiovascular System — Frequent: hemorrhage, hypertension; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. Digestive System — Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema. Endocrine System — Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. Hemic and Lymphatic System — Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia. Metabolic and Nutritional — Frequent: weight gain; Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 Musculoskeletal System — Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis. Nervous System — Frequent: agitation, amnesia, confusion, emotional lability, paresthesia, and sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder1, psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor. Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor. Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect. Urogenital System — Infrequent: abortion2, albuminuria, amenorrhea2, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation2, fibrocystic breast2, hematuria, leukorrhea2, menorrhagia2, metrorrhagia2, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage2; Rare: breast engorgement, glycosuria, hypomenorrhea2, kidney pain, oliguria, uterine hemorrhage2, uterine fibroids enlarged2. 1 Personality disorder is the COSTART term for designating non-aggressive objectionable behavior. 2 Adjusted for gender. Postintroduction Reports Voluntary reports of adverse events temporally associated with fluoxetine that have been received since market introduction of fluoxetine and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 DRUG ABUSE AND DEPENDENCE Controlled substance class — Fluoxetine is not a controlled substance. Physical and psychological dependence — Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was non-lethal. Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope. Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (see Management of Overdose). Management of Overdose Treatment should consist of those general measures employed in the management of overdosage with any SSRI. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see PRECAUTIONS). Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). DOSAGE AND ADMINISTRATION Premenstrual Dysphoric Disorder Initial Treatment The recommended dose of SARAFEM for the treatment of PMDD is 20 mg/day given continuously (every day of the menstrual cycle) or intermittently (defined as starting a daily dose 14 days prior to the anticipated onset of menstruation through the first full day of menses and repeating with each new cycle). The dosing regimen should be determined by the physician based on individual patient characteristics. In a study comparing continuous dosing of fluoxetine 20 and 60 mg/day to placebo, both doses were proven to be effective, but there was no statistically significant added benefit for the 60-mg/day compared with the 20-mg/day dose. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with PMDD. The maximum fluoxetine dose should not exceed 80 mg/day. As with many other medications, a lower or less frequent dosage should be considered in patients with hepatic impairment. A lower or less frequent dosage should also be considered for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment Systematic evaluation of SARAFEM has shown that its efficacy in PMDD is maintained for periods of up to 6 months at a dose of 20 mg/day given continuously and up to 3 months at a dose of 20 mg/day given intermittently (see CLINICAL TRIALS). Patients should be periodically reassessed to determine the need for continued treatment. Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to fluoxetine and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with fluoxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering fluoxetine in the third trimester. Discontinuation of Treatment with SARAFEM Symptoms associated with discontinuation of SARAFEM and other SSRIs and SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. HOW SUPPLIED SARAFEM® (fluoxetine hydrochloride) Pulvules®1 are available in 10-mg2 and 20-mg2 capsule strengths. The 10-mg Pulvule has an opaque lavender body and cap and is imprinted with 10 mg on the body and Sarafem on the cap: N 0430-0435-14 - Blisters of 28 The 20-mg Pulvule has an opaque pink body with opaque lavender cap and is imprinted with 20 mg on the body and Sarafem on the cap: N 0430-0436-14 - Blisters of 28 1 Pulvule and the paraboloidal shape of the capsule are registered trademarks of Eli Lilly and Company. 2 Equivalent to fluoxetine base. Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). Protect from light. Prozac® is a registered trademark of Eli Lilly and Company. ANIMAL TOXICOLOGY Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 Literature revised December 17, 2007 Manufactured by: Eli Lilly and Company Indianapolis, IN 46285, USA Marketed by: Warner Chilcott, Inc. Rockaway, NJ 07866, USA PV 5971 UCP 0435G0111 Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with your 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 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 • 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 US Food and Drug Administration for all antidepressants. Patient Information revised June 21, 2007 PV 5083 AMP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:05.681581	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018936s086lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 86}
11,378	1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PROZAC safely and effectively. See full prescribing information for PROZAC. PROZAC (fluoxetine hydrochloride) Pulvules for oral use PROZAC (fluoxetine hydrochloride) delayed-release capsules for oral use Initial U.S. Approval: 1987 WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for Major Depressive Disorder (MDD) and other psychiatric disorders (5.1). When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax. --------------------------- RECENT MAJOR CHANGES ------------------------- ------------------------INDICATIONS AND USAGE -------------------------- PROZAC® is a selective serotonin reuptake inhibitor indicated for: • Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult and pediatric patients aged 8 to 18 years (1.1) • Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in adult and pediatric patients aged 7 to 17 years (1.2) • Acute and maintenance treatment of Bulimia Nervosa in adult patients (1.3) • Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients (1.4) PROZAC and olanzapine in combination for: • Acute treatment of Depressive Episodes Associated with Bipolar I Disorder in adults (1.5) • Acute treatment of Treatment Resistant Depression in adults (Major Depressive Disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) (1.6) ----------------------- DOSAGE AND ADMINISTRATION --------------------- Indication Adult Pediatric MDD (2.1) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD (2.2) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa (2.3) 60 mg/day in am - Panic Disorder (2.4) 10 mg/day (initial dose) - Depressive Episodes Associated with Bipolar I Disorder (2.5) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) - Treatment Resistant Depression (2.6) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) - • Consider tapering the dose of fluoxetine for pregnant women during the third trimester (2.7) • A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.7) • Dosing with PROZAC Weekly capsules - initiate 7 days after the last daily dose of PROZAC 20 mg (2.1) PROZAC and olanzapine in combination: • Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability (2.5, 2.6) • Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder or treatment resistant depression (2.5, 2.6) • Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated (2.5, 2.6) ----------------------DOSAGE FORMS AND STRENGTHS -------------------- • Pulvules: 10 mg, 20 mg, 40 mg (3) • Weekly capsules: 90 mg (3) -------------------------------CONTRAINDICATIONS------------------------------ • Do not use with an MAOI or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping PROZAC before treatment with an MAOI (4, 7.1) • Do not use with pimozide due to risk of drug interaction or QTc prolongation (4, 7.9) • Do not use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing PROZAC (4, 7.9) • When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax (4) ------------------------WARNINGS AND PRECAUTIONS ---------------------- • Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1) • Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: Have been reported with PROZAC. Discontinue PROZAC and initiate supportive treatment (5.2) • Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena (5.3) • Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4) • Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.5) • Altered Appetite and Weight: Significant weight loss has occurred (5.6) • Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.7) • Hyponatremia: Has been reported with PROZAC in association with syndrome of inappropriate antidiuretic hormone (SIADH) (5.8) • Anxiety and Insomnia: May occur (5.9) • Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery (5.11) • Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks (5.12) • PROZAC and Olanzapine in Combination: When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax (5.14) -------------------------------ADVERSE REACTIONS ----------------------------- Most common adverse reactions (≥5% and at least twice that for placebo) associated with: Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1) PROZAC and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for Symbyax (6) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ------------------------------- DRUG INTERACTIONS ----------------------------- • Monoamine Oxidase Inhibitors (MAOI): PROZAC is contraindicated for use with MAOI’s, or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping PROZAC before starting treatment with an MAOI (4, 7.1) • Pimozide: PROZAC is contraindicated for use with pimozide due to risk of drug interaction or QTc prolongation (4, 7.9) • Thioridazine: PROZAC is contraindicated for use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing PROZAC (4, 7.9) • Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.9) Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 • Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with PROZAC or when PROZAC has been recently discontinued (7.9) • CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2) • Benzodiazepines: Diazepam – increased t ½ , alprazolam - further psychomotor performance decrement due to increased levels (7.9) • Antipsycotics: Potential for elevation of haloperidol and clozapine levels (7.9) • Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.9) • Serotonergic Drugs: Potential for Serotonin Syndrome (5.2, 7.3) • Triptans: There have been rare postmarketing reports of Serotonin Syndrome with use of an SSRI and a triptan (5.2, 7.4) • Tryptophan: Concomitant use with tryptophan is not recommended (5.2, 7.5) • Drugs that Interfere with Hemostasis (e.g. NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding (7.6) • Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations (7.8, 7.9) • Olanzapine: When used in combination with PROZAC, also refer to the Drug Interactions section of the package insert for Symbyax (7.9) ------------------------USE IN SPECIFIC POPULATIONS---------------------- • Pregnancy: PROZAC should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus (8.1) • Nursing Mothers: Breast feeding is not recommended (8.3) • Pediatric Use: Safety and effectiveness of PROZAC and olanzapine in combination have not been established in patients less than 18 years of age (8.4) • Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis (8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved Medication Guide Revised: [00/0000] 7.6 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, FULL PRESCRIBING INFORMATION: CONTENTS* Warfarin) WARNING — SUICIDALITY AND ANTIDEPRESSANT DRUGS 7.7 Electroconvulsive Therapy (ECT) 1 INDICATIONS AND USAGE 7.8 Potential for Other Drugs to affect PROZAC 1.1 Major Depressive Disorder 7.9 Potential for PROZAC to affect Other Drugs 1.2 Obsessive Compulsive Disorder 8 USE IN SPECIFIC POPULATIONS 1.3 Bulimia Nervosa 8.1 Pregnancy 1.4 Panic Disorder 8.2 Labor and Delivery 1.5 PROZAC and Olanzapine in Combination: Depressive Episodes 8.3 Nursing Mothers Associated with Bipolar I Disorder 8.4 Pediatric Use 1.6 PROZAC and Olanzapine in Combination: Treatment Resistant 8.5 Geriatric Use Depression 8.6 Hepatic Impairment 2 DOSAGE AND ADMINISTRATION 9 DRUG ABUSE AND DEPENDENCE 2.1 Major Depressive Disorder 9.3 Dependence 2.2 Obsessive Compulsive Disorder 10 OVERDOSAGE 2.3 Bulimia Nervosa 10.1 Human Experience 2.4 Panic Disorder 10.2 Animal Experience 2.5 PROZAC and Olanzapine in Combination: Depressive Episodes 10.3 Management of Overdose Associated with Bipolar I Disorder 2.6 PROZAC and Olanzapine in Combination: Treatment Resistant 11 DESCRIPTION Depression 12 CLINICAL PHARMACOLOGY 2.7 Dosing in Specific Populations 12.1 Mechanism of Action 2.8 Discontinuation of Treatment 12.2 Pharmacodynamics 3 DOSAGE FORMS AND STRENGTHS 12.3 Pharmacokinetics 12.4 Specific Populations 4 CONTRAINDICATIONS 13 NONCLINICAL TOXICOLOGY 5 WARNINGS AND PRECAUTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.1 Clinical Worsening and Suicide Risk 13.2 Animal Toxicology and/or Pharmacology 5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions 14 CLINICAL STUDIES 5.3 Allergic Reactions and Rash 14.1 Major Depressive Disorder 5.4 Screening Patients for Bipolar Disorder and Monitoring for 14.2 Obsessive Compulsive Disorder Mania/Hypomania 14.3 Bulimia Nervosa 5.5 Seizures 14.4 Panic Disorder 5.6 Altered Appetite and Weight 16 HOW SUPPLIED/STORAGE AND HANDLING 5.7 Abnormal Bleeding 16.1 How Supplied 5.8 Hyponatremia 16.2 Storage and Handling 5.9 Anxiety and Insomnia 17 PATIENT COUNSELING INFORMATION 5.10 Use in Patients with Concomitant Illness 17.1 General Information 5.11 Potential for Cognitive and Motor Impairment 17.2 Clinical Worsening and Suicide Risk 5.12 Long Elimination Half-Life 17.3 Serotonin Syndrome or Neuroleptic Malignant Syndrome 5.13 Discontinuation of Treatment (NMS)-like Reactions 5.14 PROZAC and Olanzapine in Combination 17.4 Allergic Reactions and Rash 6 ADVERSE REACTIONS 17.5 Abnormal Bleeding 6.1 Clinical Trials Experience 17.6 Hyponatremia 6.2 Other Reactions 17.7 Potential for Cognitive and Motor Impairment 6.3 Postmarketing Experience 17.8 Use of Concomitant Medications 7 DRUG INTERACTIONS 17.9 Discontinuation of Treatment 7.1 Monoamine Oxidase Inhibitors (MAOI) 17.10 Use in Specific Populations 7.2 CNS Acting Drugs *Sections or subsections omitted from the full prescribing information are not 7.3 Serotonergic Drugs listed 7.4 Triptans 7.5 Tryptophan Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 FULL PRESCRIBING INFORMATION WARNING: 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 PROZAC 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. PROZAC is approved for use in pediatric patients with MDD and Obsessive Compulsive Disorder (OCD) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax. 1 INDICATIONS AND USAGE 1.1 Major Depressive Disorder PROZAC® is indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to 18 years [see Clinical Studies (14.1)]. The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods, should periodically be re evaluated [see Dosage and Administration (2.1)]. 1.2 Obsessive Compulsive Disorder PROZAC is indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2)]. The effectiveness of PROZAC in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use PROZAC for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.2)]. 1.3 Bulimia Nervosa PROZAC is indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)]. The physician who elects to use PROZAC for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)]. 1.4 Panic Disorder PROZAC is indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [see Clinical Studies (14.4)]. The effectiveness of PROZAC in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use PROZAC for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.4)]. 1.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax® . PROZAC and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder in adult patients. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. 1.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. PROZAC and olanzapine in combination is indicated for the acute treatment of treatment resistant depression (Major Depressive Disorder in adult patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode). PROZAC monotherapy is not indicated for the treatment of treatment resistant depression. 2 DOSAGE AND ADMINISTRATION 2.1 Major Depressive Disorder Initial Treatment Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies (14.1)]. Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Daily Dosing — Systematic evaluation of PROZAC in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day [see Clinical Studies (14.1)]. Weekly Dosing — Systematic evaluation of PROZAC® Weekly™ in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment with PROZAC 20 mg once daily. However, therapeutic equivalence of PROZAC Weekly given on a once-weekly basis with PROZAC 20 mg given daily for delaying time to relapse has not been established [see Clinical Studies (14.1)]. Weekly dosing with PROZAC Weekly capsules is recommended to be initiated 7 days after the last daily dose of PROZAC 20 mg [see Clinical Pharmacology (12.3)]. If satisfactory response is not maintained with PROZAC Weekly, consider reestablishing a daily dosing regimen [see Clinical Studies (14.1)]. Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Drug Interactions (7.9)]. Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) — At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with PROZAC. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping PROZAC before starting an MAOI [see Contraindications (4) and Drug Interactions (7.1)]. 2.2 Obsessive Compulsive Disorder Initial Treatment Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)]. In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue PROZAC, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of PROZAC after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. 2.3 Bulimia Nervosa Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo [see Clinical Studies (14.3)]. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. Maintenance/Continuation Treatment — Systematic evaluation of continuing PROZAC 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking PROZAC 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment [see Clinical Studies (14.3)]. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. 2.4 Panic Disorder Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.4)]. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue PROZAC, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. 2.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. Table 1: Approximate Dose Correspondence Between Symbyax1 and the Combination of PROZAC and Olanzapine For Symbyax (mg/day) Use in Combination Olanzapine (mg/day) PROZAC (mg/day) 3 mg olanzapine/25 mg fluoxetine 2.5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 1 Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of PROZAC and olanzapine. While there is no body of evidence to answer the question of how long a patient treated with PROZAC and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. 2.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 20 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. While there is no body of evidence to answer the question of how long a patient treated with PROZAC and olanzapine in combination should remain on it, it is generally accepted that treatment resistant depression (Major Depressive Disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. PROZAC monotherapy is not indicated for the treatment of treatment resistant depression (Major Depressive Disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode). 2.7 Dosing in Specific Populations Treatment of Pregnant Women during the Third Trimester — When treating pregnant women with PROZAC during the third trimester, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. The physician may consider tapering PROZAC in the third trimester [see Use in Specific Populations (8.1)]. Geriatric — A lower or less frequent dosage should be considered for the elderly [see Use in Specific Populations (8.5)] Hepatic Impairment — As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment [see Clinical Pharmacology (12.4) and Use in Specific Populations (8.6)]. Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology (12.4) and Warnings and Precautions (5.10)]. PROZAC and Olanzapine in Combination — The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modifications may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. PROZAC and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 18 years of age [see Warnings and Precautions (5.14) and Drug Interactions (7.9)]. 2.8 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.13)]. 3 DOSAGE FORMS AND STRENGTHS • 10 mg Pulvule is an opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body • 20 mg Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body • 40 mg Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body • 90 mg Prozac Weekly™ Capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body 4 CONTRAINDICATIONS When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. The use of PROZAC is contraindicated with the following: • Monoamine Oxidase Inhibitors [see Drug Interactions (7.1)] • Pimozide [see Drug Interactions (7.9)] • Thioridazine [see Drug Interactions (7.9)] 5 WARNINGS AND PRECAUTIONS When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. 5.1 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 Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 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 versus 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 2. Table 2: Suicidality per 1000 Patients Treated 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. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.13)]. 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 PROZAC should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. It should be noted that PROZAC is approved in the pediatric population only for Major Depressive Disorder and Obsessive Compulsive Disorder. Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 18 years of age have not been established. 5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including PROZAC treatment, but particularly with concomitant use of Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS- like signs and symptoms. The concomitant use of PROZAC with MAOIs intended to treat depression is contraindicated [see Contraindications (4) and Drug Interactions (7.1)]. If concomitant treatment of PROZAC with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions (7.4)]. The concomitant use of PROZAC with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions (7.3)]. Treatment with fluoxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. 5.3 Allergic Reactions and Rash In US fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely. In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of PROZAC, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions. Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom. Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, PROZAC should be discontinued. 5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 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 for clinical worsening and suicide risk 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 PROZAC and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions section of the package insert for Symbyax]. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with PROZAC and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see Use in Specific Populations (8.4)]. In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with PROZAC and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In US PROZAC clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)]. 5.5 Seizures In US placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with PROZAC and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In US PROZAC clinical trials, 0.2% of 10,782 patients Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. PROZAC should be introduced with care in patients with a history of seizures. 5.6 Altered Appetite and Weight Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with PROZAC. In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with PROZAC and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with PROZAC and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with PROZAC because of anorexia or weight loss [see Use in Specific Populations (8.4)]. In US placebo-controlled clinical trials for OCD, 17% of patients treated with PROZAC and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with PROZAC because of anorexia [see Use in Specific Populations (8.4)]. In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with PROZAC 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with PROZAC 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy. 5.7 Abnormal Bleeding SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.6)]. 5.8 Hyponatremia Hyponatremia has been reported during treatment with SNRIs and SSRIs, including PROZAC. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when PROZAC was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of PROZAC should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.9 Anxiety and Insomnia In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with PROZAC and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with PROZAC and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with PROZAC and in 7% of patients treated with placebo. In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with PROZAC 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with PROZAC 60 mg and in 9% and 5% of patients treated with placebo. Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5]. 5.10 Use in Patients with Concomitant Illness Clinical experience with PROZAC in patients with concomitant systemic illness is limited. Caution is advisable in using PROZAC in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received PROZAC in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. Glycemic Control — In patients with diabetes, PROZAC may alter glycemic control. Hypoglycemia has occurred during therapy with PROZAC, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with PROZAC is instituted or discontinued. 5.11 Potential for Cognitive and Motor Impairment As with any CNS-active drug, PROZAC has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. 5.12 Long Elimination Half-Life Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see Clinical Pharmacology (12.3)]. 5.13 Discontinuation of Treatment During marketing of PROZAC, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with PROZAC. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. 5.14 PROZAC and Olanzapine in Combination When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. 6 ADVERSE REACTIONS When using PROZAC and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of PROZAC have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered PROZAC in panic clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that reactions reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use of PROZAC (incidence of at least 5% for PROZAC and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, OCD, and bulimia in US controlled clinical trials and Panic Disorder in US plus non-US controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with PROZAC and with incidence greater than placebo who participated in US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3. Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Table 3: Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1,2 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Reaction PROZAC (N=1728) Placebo (N=975) PROZAC (N=266) Placebo (N=89) PROZAC (N=450) Placebo (N=267) PROZAC (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 - 2 1 1 - Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 - 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 - 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence3 2 -- -- -- 7 -- 1 -- Abnormal ejaculation3 -- -- 7 -- 7 -- 2 1 1 Incidence less than 1%. 2 Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. 3 Denominator used was for males only (N=690 PROZAC Major Depressive Disorder; N=410 placebo Major Depressive Disorder; N=116 PROZAC OCD; N=43 placebo OCD; N=14 PROZAC bulimia; N=1 placebo bulimia; N=162 PROZAC panic; N=121 placebo panic). Table 4: Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1,2 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 and Panic Disorder Combined Body System/ Adverse Reaction PROZAC (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 1 Incidence less than 1%. 2 Includes US data for Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 5 lists the adverse reactions associated with discontinuation of PROZAC treatment (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials. Table 5: Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- - Nervousness (1%) - - Nervousness (1%) -- -- Rash (1%) -- -- 1 Includes US Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials. Other adverse reactions in pediatric patients (children and adolescents) — Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected. Reactions observed in PROZAC Weekly clinical trials — Treatment-emergent adverse reactions in clinical trials with PROZAC Weekly were similar to the adverse reactions reported by patients in clinical trials with PROZAC daily. In a placebo-controlled clinical trial, more patients taking PROZAC Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking PROZAC 20 mg daily (10% versus 5%, respectively). Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. 6.2 Other Reactions Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction. Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia, hypotension1. Digestive System — Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage. Hemic and Lymphatic System — Infrequent: ecchymosis; Rare: petechia, purpura. Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder1, bruxism1, buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions. Respiratory System — Rare: larynx edema. Skin and Appendages — Infrequent: alopecia; Rare: purpuric rash. Special Senses — Frequent: taste perversion; Infrequent: mydriasis. Urogenital System — Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding2 . 1 MedDRA dictionary term from integrated database of placebo controlled trials of 15870 patients, of which 9673 patients received fluoxetine. Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of PROZAC. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with PROZAC that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including torsades de pointes–type arrhythmias), vaginal bleeding, and violent behaviors1. 1 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. 7 DRUG INTERACTIONS As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. 7.1 Monoamine Oxidase Inhibitors (MAOI) There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, PROZAC should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Contraindications (4)]. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should be allowed after stopping PROZAC before starting an MAOI [see Clinical Pharmacology (12.3)]. 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of PROZAC and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)]. 7.3 Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including PROZAC, and the potential for serotonin syndrome, caution is advised when PROZAC is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort [see Warnings and Precautions (5.2)]. The concomitant use of PROZAC with SNRIs, SSRIs, or tryptophan is not recommended [see Drug Interactions (7.4), (7.5)]. 7.4 Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of PROZAC with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.2) and Drug Interactions (7.3)]. 7.5 Tryptophan Five patients receiving PROZAC in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. The concomitant use with tryptophan is not recommended [see Warnings and Precautions (5.2) and Drug Interactions (7.3)]. 7.6 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7)]. 7.7 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. 7.8 Potential for Other Drugs to affect PROZAC Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs [see Clinical Pharmacology (12.3)]. 7.9 Potential for PROZAC to affect Other Drugs Pimozide — Concomitant use in patients taking pimozide is contraindicated. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and PROZAC [see Contraindications (4)]. Thioridazine — Thioridazine should not be administered with PROZAC or within a minimum of 5 weeks after PROZAC has been discontinued [see Contraindications (4)]. In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine. Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Drugs Metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4)]. Tricyclic Antidepressants (TCAs) — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Clinical Pharmacology (12.3)]. Benzodiazapines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine [see Contraindications (4)]. Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect [see Clinical Pharmacology (12.3)]. Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Olanzapine— Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using PROZAC and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax. 8 USE IN SPECIFIC POPULATIONS When using PROZAC and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. 8.1 Pregnancy Pregnancy Category C — PROZAC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. Treatment of Pregnant Women during the First Trimester — There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1,359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. Treatment of Pregnant Women during the Third Trimester — Neonates exposed to PROZAC, SNRIs, or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SNRIs and SSRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. Clinical Considerations — When treating pregnant women with PROZAC, the physician should carefully consider both the potential risks and potential benefits of treatment, taking into account the risk of untreated depression during pregnancy. Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. The physician may consider tapering PROZAC in the third trimester [see Dosage and Administration (2.7)]. Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). 8.2 Labor and Delivery The effect of PROZAC on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Because PROZAC is excreted in human milk, nursing while on PROZAC is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on PROZAC developed crying, sleep Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. 8.4 Pediatric Use The efficacy of PROZAC for the treatment of Major Depressive Disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 [see Clinical Studies (14.1)]. The efficacy of PROZAC for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 [see Clinical Studies (14.2)]. The safety and effectiveness in pediatric patients <8 years of age in Major Depressive Disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with Major Depressive Disorder or OCD [see Clinical Pharmacology (12.3)]. The acute adverse reaction profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19-week Major Depressive Disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see Adverse Reactions (6.1)]. Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. [see Warnings and Precautions (5.6)]. PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Anyone considering the use of PROZAC in a child or adolescent must balance the potential risks with the clinical need. Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis. In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increase shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain. Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 18 years of age have not been established. Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 8.5 Geriatric Use US fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.4)]. No overall differences in safety or 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. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.8)]. Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using PROZAC in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.7) and Clinical Pharmacology (12.4)]. 9 DRUG ABUSE AND DEPENDENCE 9.3 Dependence PROZAC has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with PROZAC did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of PROZAC (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). 10 OVERDOSAGE 10.1 Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope. 10.2 Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see Overdosage (10.3)]. 10.3 Management of Overdose Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of Major Depressive Disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Drug Interactions (7. 9)]. Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert. 11 DESCRIPTION PROZAC® (fluoxetine capsules, USP) is a selective serotonin reuptake inhibitor for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3 [(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: s tructural formula CHCH2CH2NHCH3 • HCl Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol), 20 mg (64.7 µmol), or 40 mg (129.3 µmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10 and 20 mg Pulvules also contain FD&C Blue No. 1, and the 40 mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. PROZAC Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 µmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Although the exact mechanism of PROZAC is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. 12.2 Pharmacodynamics Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. 12.3 Pharmacokinetics Systemic Bioavailability — In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The Pulvule and PROZAC Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. PROZAC Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 Protein Binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important. Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions (7.9)]. Accumulation and Slow Elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used [see Warnings and Precautions (5.12)]. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of PROZAC. Weekly Dosing — Administration of PROZAC Weekly once weekly results in increased fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of clinical response. Peak concentrations from once-weekly doses of PROZAC Weekly capsules of fluoxetine are in the range of the average concentration for 20 mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20 mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly dosing are in relative proportion to the total dose administered. Average steady-state fluoxetine concentrations are approximately 50% lower following the once-weekly regimen compared with the once-daily regimen. Cmax for fluoxetine following the 90 mg dose was approximately 1.7-fold higher than the Cmax value for the established 20 mg once-daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90 mg once-weekly dose and the last 20 mg once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better to separate the first 90 mg weekly dose and the last 20 mg once-daily dose by 1 week [see Dosage and Administration (2.1)]. 12.4 Specific Populations Liver Disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used [see Dosage and Administration (2.7), Use in Specific Populations (8.6)]. Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 Renal Disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. Geriatric Pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients. Pediatric Pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with Major Depressive Disorder or Obsessive Compulsive Disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with Major Depressive Disorder. Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity. Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of Fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)]. 13.2 Animal Toxicology and/or Pharmacology Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. 14 CLINICAL STUDIES When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. 14.1 Major Depressive Disorder Daily Dosing Adult — The efficacy of PROZAC was studied in 5- and 6-week placebo-controlled trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of Major Depressive Disorder. PROZAC was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). PROZAC was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. Two 6-week controlled studies (N=671, randomized) comparing PROZAC 20 mg and placebo have shown PROZAC 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with Major Depressive Disorder. In these studies, PROZAC produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. PROZAC was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between PROZAC (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on PROZAC 20 mg/day. These patients (N=298) were randomized to continuation on double-blind Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 PROZAC 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking PROZAC compared with those on placebo. Pediatric (children and adolescents) — The efficacy of PROZAC 20 mg/day in children and adolescents (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) was studied in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of Major Depressive Disorder. In both studies independently, PROZAC produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Weekly dosing for Maintenance/Continuation Treatment A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for Major Depressive Disorder who had responded (defined as having a modified HAMD-17 score of ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for Major Depressive Disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with PROZAC 20 mg once daily. These patients were randomized to double-blind, once-weekly continuation treatment with PROZAC Weekly, PROZAC 20 mg once daily, or placebo. PROZAC Weekly once weekly and PROZAC 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of depressive symptoms) compared with placebo for a period of 25 weeks. However, the equivalence of these 2 treatments during continuation therapy has not been established. 14.2 Obsessive Compulsive Disorder Adult — The effectiveness of PROZAC for the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed PROZAC doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving PROZAC experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving PROZAC experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: Table 6 Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies PROZAC Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD (DSM-IV), patients received PROZAC 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. PROZAC produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. 14.3 Bulimia Nervosa The effectiveness of PROZAC for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of PROZAC or placebo in the morning. Patients in the 16-week study received a fixed PROZAC dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, PROZAC 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________ 23 PROZAC-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between PROZAC 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with PROZAC 60 mg/day, were randomized to continuation of PROZAC 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued PROZAC 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. 14.4 Panic Disorder The effectiveness of PROZAC in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia. Study 1 (N=180 randomized) was a 12-week flexible-dose study. PROZAC was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of PROZAC-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N=214 randomized) was a 12-week flexible-dose study. PROZAC was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of PROZAC-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied The following products are manufactured by Eli Lilly and Company for Dista Products Company: Pulvule are available in 10mg, 20mg and 40mg capsule strengths and packages as follows: Pulvule Strength 10 mg1 20 mg1 40 mg1 Pulvule No.2 PU3104 PU3105 PU3107 Cap Color Opaque green Opaque green Opaque green Body Color Opaque green Opaque yellow Opaque orange Identification DISTA 3104 Prozac 10 mg DISTA 3105 Prozac 20 mg DISTA 3107 Prozac 40 mg NDC Codes: Bottles of 30 0777-3105-30 0777-3107-30 Bottles 100 0777-3104-02 0777-3105-02 Bottles of 2000 0777-3105-07 The following product is manufactured and distributed by Eli Lilly and Company: PROZAC® Weekly™ Capsules are available in: The 90 mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) – Blister package of 4 1 Fluoxetine base equivalent. 2 Protect from light. 16.2 Storage and Handling Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). 17 PATIENT COUNSELING INFORMATION See the FDA-approved Medication Guide. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking PROZAC as monotherapy or in combination with olanzapine. When using PROZAC and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax. 17.1 General Information Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with PROZAC and to reread it each time the prescription is renewed. Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with PROZAC and should counsel them in its appropriate use. Healthcare providers 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. Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking PROZAC. When using PROZAC and olanzapine in combination, also refer to the Medication Guide for Symbyax. 17.2 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 [see Box Warning and Warnings and Precautions (5.1)]. 17.3 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions Patients should be cautioned about the risk of serotonin syndrome or NMS-like reactions with the concomitant use of PROZAC and triptans, tramadol, or other serotonergic agents [see Warnings and Precautions (5.2) and Drug Interactions (7.3)]. Patients should be advised of the signs and symptoms associated with serotonin syndrome or NMS-like reactions that may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, in which the symptoms may include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be cautioned to seek medical care immediately if they experience these symptoms. 17.4 Allergic Reactions and Rash Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions (5.3)]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms. 17.5 Abnormal Bleeding Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see Warnings and Precautions (5.7) and Drug Interactions (7.6)]. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking PROZAC. 17.6 Hyponatremia Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including PROZAC. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions (5.8)]. 17.7 Potential for Cognitive and Motor Impairment PROZAC may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions (5.11)]. 17.8 Use of Concomitant Medications Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax, Sarafem, or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on PROZAC. 17.9 Discontinuation of Treatment Patients should be advised to take PROZAC exactly as prescribed, and to continue taking PROZAC as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking PROZAC without consulting their physician [see Warnings and Precautions (5.13)]. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with PROZAC. 17.10 Use in Specific Populations Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. Nursing Mothers — Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy. Because PROZAC is excreted in human milk, nursing while taking PROZAC is not recommended [see Use in Specific Populations (8.3)]. Pediatric Use — PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine. Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 18 years of age have not been established [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)]. Literature revised Month dd, yyyy Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 1987, XXXX, Eli Lilly and Company. All rights reserved. A4.0 NL 7430 DPP Reference ID: 2927282 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:06.000149	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018936s091lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 91}
11,377	1 1.0 NL PV 5327 DPP 2 PROZAC® 3 FLUOXETINE CAPSULES, USP 4 FLUOXETINE ORAL SOLUTION, USP 5 FLUOXETINE DELAYED-RELEASE CAPSULES, USP 6 WARNING 7 Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to 8 placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young 9 adults in short-term studies of major depressive disorder (MDD) and other psychiatric 10 disorders. Anyone considering the use of Prozac or any other antidepressant in a child, 11 adolescent, or young adult must balance this risk with the clinical need. Short-term studies 12 did not show an increase in the risk of suicidality with antidepressants compared to 13 placebo in adults beyond age 24; there was a reduction in risk with antidepressants 14 compared to placebo in adults aged 65 and older. Depression and certain other psychiatric 15 disorders are themselves associated with increases in the risk of suicide. Patients of all ages 16 who are started on antidepressant therapy should be monitored appropriately and 17 observed closely for clinical worsening, suicidality, or unusual changes in behavior. 18 Families and caregivers should be advised of the need for close observation and 19 communication with the prescriber. Prozac is approved for use in pediatric patients with 20 MDD and obsessive compulsive disorder (OCD). (See WARNINGS, Clinical Worsening 21 and Suicide Risk, PRECAUTIONS, Information for Patients, and PRECAUTIONS, 22 Pediatric Use.) 23 DESCRIPTION 24 Prozac® (fluoxetine capsules, USP and fluoxetine oral solution, USP) is a psychotropic drug 25 for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder 26 (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α 27 trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of 28 C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: 1 Str uct ural Formula 31 in water. 32 Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 33 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The Pulvules also contain starch, 34 gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- and 20-mg 35 Pulvules also contain FD&C Blue No. 1, and the 40-mg Pulvule also contains FD&C Blue No. 1 36 and FD&C Yellow No. 6. 37 The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 μmol) of 38 fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, 39 and sucrose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 40 Prozac Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of 41 fluoxetine hydrochloride equivalent to 90 mg (291 μmol) of fluoxetine. The capsules also 42 contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate 43 succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, 44 and other inactive ingredients. 45 CLINICAL PHARMACOLOGY 46 47 Pharmacodynamics The antidepressant, antiobsessive compulsive, and antibulimic actions of fluoxetine are 48 presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically 49 relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into 50 human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake 51 inhibitor of serotonin than of norepinephrine. 52 Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized 53 to be associated with various anticholinergic, sedative, and cardiovascular effects of classical 54 tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors 55 from brain tissue much less potently in vitro than do the tricyclic drugs. 56 57 Absorption, Distribution, Metabolism, and Excretion Systemic bioavailability — In man, following a single oral 40-mg dose, peak plasma 58 concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. 59 The Pulvule, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are 60 bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although 61 it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, 62 fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayed-release 63 formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the 64 gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of 65 absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. 66 Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 67 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and 68 α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has 69 not been fully evaluated, but may be important (see PRECAUTIONS). 70 Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine 71 enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake 72 inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is 73 eliminated more slowly and is the predominant enantiomer present in plasma at steady state. 74 Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a 75 number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is 76 formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and 77 selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or 78 S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of 79 serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive 80 metabolites excreted by the kidney. 81 Clinical issues related to metabolism/elimination — The complexity of the metabolism of 82 fluoxetine has several consequences that may potentially affect fluoxetine’s clinical use. 83 Variability in metabolism — A subset (about 7%) of the population has reduced activity of the 84 drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 85 “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study 86 involving labeled and unlabeled enantiomers administered as a racemate, these individuals 87 metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of 88 S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The 89 metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with 90 normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active 91 enantiomers was not significantly greater among poor metabolizers. Thus, the net 92 pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways 93 (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine 94 achieves a steady-state concentration rather than increasing without limit. 95 Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs 96 and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, 97 concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may 98 lead to drug interactions (see Drug Interactions under PRECAUTIONS). 99 Accumulation and slow elimination — The relatively slow elimination of fluoxetine 100 (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic 101 administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after 102 acute and chronic administration), leads to significant accumulation of these active species in 103 chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days 104 of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and 105 norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of 106 fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s 107 metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear 108 pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple 109 dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 110 weeks. 111 The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing 112 is stopped, active drug substance will persist in the body for weeks (primarily depending on 113 individual patient characteristics, previous dosing regimen, and length of previous therapy at 114 discontinuation). This is of potential consequence when drug discontinuation is required or when 115 drugs are prescribed that might interact with fluoxetine and norfluoxetine following the 116 discontinuation of Prozac. 117 Weekly dosing — Administration of Prozac Weekly once weekly results in increased 118 fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared 119 with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 120 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of 121 clinical response. Peak concentrations from once-weekly doses of Prozac Weekly capsules of 122 fluoxetine are in the range of the average concentration for 20-mg once-daily dosing. Average 123 trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the 124 concentrations maintained by 20-mg once-daily dosing. Average steady-state concentrations of 125 either once-daily or once-weekly dosing are in relative proportion to the total dose administered. 126 Average steady-state fluoxetine concentrations are approximately 50% lower following the 127 once-weekly regimen compared with the once-daily regimen. 128 Cmax for fluoxetine following the 90-mg dose was approximately 1.7-fold higher than the Cmax 129 value for the established 20-mg once-daily regimen following transition the next day to the 130 once-weekly regimen. In contrast, when the first 90-mg once-weekly dose and the last 20-mg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 131 once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient 132 increase in the average steady-state concentrations of fluoxetine observed following transition 133 the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better 134 to separate the first 90-mg weekly dose and the last 20-mg once-daily dose by 1 week (see 135 DOSAGE AND ADMINISTRATION). 136 Liver disease — As might be predicted from its primary site of metabolism, liver impairment 137 can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in 138 a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen 139 in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean 140 duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal 141 subjects. This suggests that the use of fluoxetine in patients with liver disease must be 142 approached with caution. If fluoxetine is administered to patients with liver disease, a lower or 143 less frequent dose should be used (see PRECAUTIONS and DOSAGE AND 144 ADMINISTRATION). 145 Renal disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg 146 once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma 147 concentrations comparable with those seen in patients with normal renal function. While the 148 possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels 149 in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely 150 necessary in renally impaired patients (see Use in Patients with Concomitant Illness under 151 PRECAUTIONS and DOSAGE AND ADMINISTRATION). 152 Age 153 Geriatric pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly 154 subjects (>65 years of age) did not differ significantly from that in younger normal subjects. 155 However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not 156 adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they 157 have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age 158 upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy 159 depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined 160 fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 161 weeks. No unusual age-associated pattern of adverse events was observed in those elderly 162 patients. 163 Pediatric pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were 164 evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) 165 diagnosed with major depressive disorder or obsessive compulsive disorder (OCD). Fluoxetine 166 20 mg/day was administered for up to 62 days. The average steady-state concentrations of 167 fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, 168 respectively). The average norfluoxetine steady-state concentrations in these children were 169 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be 170 almost entirely explained by differences in weight. No gender-associated difference in fluoxetine 171 pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma 172 concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed 173 with major depressive disorder. 174 Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in 175 children relative to adults; however, these concentrations were within the range of concentrations 176 observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 177 extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 178 4 weeks of daily dosing. 179 CLINICAL TRIALS 180 Major Depressive Disorder 181 Daily Dosing 182 Adult — The efficacy of Prozac for the treatment of patients with major depressive disorder 183 (≥18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac was 184 shown to be significantly more effective than placebo as measured by the Hamilton Depression 185 Rating Scale (HAM-D). Prozac was also significantly more effective than placebo on the 186 HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. 187 Two 6-week controlled studies (N=671, randomized) comparing Prozac 20 mg and placebo 188 have shown Prozac 20 mg daily to be effective in the treatment of elderly patients (≥60 years of 189 age) with major depressive disorder. In these studies, Prozac produced a significantly higher rate 190 of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a 191 total endpoint HAM-D score of ≤8. Prozac was well tolerated and the rate of treatment 192 discontinuations due to adverse events did not differ between Prozac (12%) and placebo (9%). 193 A study was conducted involving depressed outpatients who had responded (modified 194 HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of 195 major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week 196 open-treatment phase on Prozac 20 mg/day. These patients (N=298) were randomized to 197 continuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), a 198 statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis 199 of major depressive disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was 200 observed for patients taking Prozac compared with those on placebo. 201 Pediatric (children and adolescents) — The efficacy of Prozac 20 mg/day for the treatment of 202 major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to 203 <13, 145 adolescents ages 13 to ≤18) has been studied in two 8- to 9-week placebo-controlled 204 clinical trials. 205 In both studies independently, Prozac produced a statistically significantly greater mean 206 change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline 207 to endpoint than did placebo. 208 Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness 209 on the basis of age or gender. 210 Weekly dosing for maintenance/continuation treatment 211 A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for 212 major depressive disorder who had responded (defined as having a modified HAMD-17 score of 213 ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for major depressive disorder) for 214 3 consecutive weeks at the end of 13 weeks of open-label treatment with Prozac 20 mg once 215 daily. These patients were randomized to double-blind, once-weekly continuation treatment with 216 Prozac Weekly, Prozac 20 mg once daily, or placebo. Prozac Weekly once weekly and Prozac 217 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of 218 depressive symptoms) compared with placebo for a period of 25 weeks. However, the 219 equivalence of these 2 treatments during continuation therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 220 Obsessive Compulsive Disorder 221 Adult — The effectiveness of Prozac for the treatment of obsessive compulsive disorder 222 (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of 223 adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once-a-day 224 schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD 225 (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale 226 (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced 227 mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit 228 reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean 229 reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit 230 reduction for placebo patients. While there was no indication of a dose-response relationship for 231 effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically 232 better responses in the 2 higher dose groups. The following table provides the outcome 233 classification by treatment group on the Clinical Global Impression (CGI) improvement scale for 234 Studies 1 and 2 combined: 235 236 Outcome Classification (%) on CGI Improvement Scale for 237 Completers in Pool of Two OCD Studies Prozac Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% 238 239 Exploratory analyses for age and gender effects on outcome did not suggest any differential 240 responsiveness on the basis of age or sex. 241 Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients 242 (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD, 243 patients received Prozac 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose 244 was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and 245 tolerability. Prozac produced a statistically significantly greater mean change from baseline to 246 endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive 247 Scale (CY-BOCS). 248 Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of 249 age or gender. 250 Bulimia Nervosa 251 The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8-week and 252 one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria 253 for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of Prozac or placebo 254 in the morning. Patients in the 16-week study received a fixed Prozac dose of 60 mg/day (once a 255 day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median 256 binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, 257 respectively. In these 3 studies, Prozac 60 mg, but not 20 mg, was statistically significantly 258 superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The 259 statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 260 and persisted throughout each study. The Prozac-related reduction in bulimic episodes appeared 261 to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. 262 In each of these 3 studies, the treatment effect, as measured by differences between Prozac 263 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at 264 endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for 265 vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in 266 patients with higher baseline frequencies. Although some patients achieved freedom from 267 binge-eating and purging as a result of treatment, for the majority, the benefit was a partial 268 reduction in the frequency of binge-eating and purging. 269 In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging 270 subtype, who had responded during a single-blind, 8-week acute treatment phase with Prozac 271 60 mg/day, were randomized to continuation of Prozac 60 mg/day or placebo, for up to 52 weeks 272 of observation for relapse. Response during the single-blind phase was defined by having 273 achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during 274 the double-blind phase was defined as a persistent return to baseline vomiting frequency or 275 physician judgment that the patient had relapsed. Patients receiving continued Prozac 60 mg/day 276 experienced a significantly longer time to relapse over the subsequent 52 weeks compared with 277 those receiving placebo. 278 Panic Disorder 279 The effectiveness of Prozac in the treatment of panic disorder was demonstrated in 2 280 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a 281 primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia. 282 Study 1 (N=180 randomized) was a 12-week flexible-dose study. Prozac was initiated at 283 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on 284 the basis of clinical response and tolerability. A statistically significantly greater percentage of 285 Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 286 42% versus 28%, respectively. 287 Study 2 (N=214 randomized) was a 12-week flexible-dose study. Prozac was initiated at 288 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on 289 the basis of clinical response and tolerability. A statistically significantly greater percentage of 290 Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 291 62% versus 44%, respectively. 292 INDICATIONS AND USAGE 293 Major Depressive Disorder 294 Prozac is indicated for the treatment of major depressive disorder. 295 Adult — The efficacy of Prozac was established in 5- and 6-week trials with depressed adult 296 and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the 297 DSM-III (currently DSM-IV) category of major depressive disorder (see CLINICAL TRIALS). 298 A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly 299 every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily 300 functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of 301 interest in usual activities, significant change in weight and/or appetite, insomnia or 302 hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or 303 worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. 304 The effects of Prozac in hospitalized depressed patients have not been adequately studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 305 The efficacy of Prozac 20 mg once daily in maintaining a response in major depressive 306 disorder for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) 307 was demonstrated in a placebo-controlled trial. 308 The efficacy of Prozac Weekly once weekly in maintaining a response in major depressive 309 disorder has been demonstrated in a placebo-controlled trial for up to 25 weeks following 310 open-label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38 311 weeks. However, it is unknown whether or not Prozac Weekly given on a once-weekly basis 312 provides the same level of protection from relapse as that provided by Prozac 20 mg daily 313 (see CLINICAL TRIALS). 314 Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was 315 established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose 316 diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive 317 disorder (see CLINICAL TRIALS). 318 The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended 319 periods should be reevaluated periodically. 320 Obsessive Compulsive Disorder 321 Adult — Prozac is indicated for the treatment of obsessions and compulsions in patients with 322 obsessive compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or 323 compulsions cause marked distress, are time-consuming, or significantly interfere with social or 324 occupational functioning. 325 The efficacy of Prozac was established in 13-week trials with obsessive compulsive outpatients 326 whose diagnoses corresponded most closely to the DSM-III-R category of OCD (see CLINICAL 327 TRIALS). 328 OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images 329 (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors 330 (compulsions) that are recognized by the person as excessive or unreasonable. 331 The effectiveness of Prozac in long-term use, i.e., for more than 13 weeks, has not been 332 systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use 333 Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug 334 for the individual patient (see DOSAGE AND ADMINISTRATION). 335 Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was 336 established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in 337 DSM-IV (see CLINICAL TRIALS). 338 Bulimia Nervosa 339 Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with 340 moderate to severe bulimia nervosa. 341 The efficacy of Prozac was established in 8- to 16-week trials for adult outpatients with 342 moderate to severe bulimia nervosa, i.e., at least 3 bulimic episodes per week for 6 months (see 343 CLINICAL TRIALS). 344 The efficacy of Prozac 60 mg/day in maintaining a response, in patients with bulimia who 345 responded during an 8-week acute treatment phase while taking Prozac 60 mg/day and were then 346 observed for relapse during a period of up to 52 weeks, was demonstrated in a placebo-controlled 347 trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Prozac for 348 extended periods should periodically reevaluate the long-term usefulness of the drug for the 349 individual patient (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 9 350 Panic Disorder 351 Prozac is indicated for the treatment of panic disorder, with or without agoraphobia, as defined 352 in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks, and 353 associated concern about having additional attacks, worry about the implications or 354 consequences of the attacks, and/or a significant change in behavior related to the attacks. 355 The efficacy of Prozac was established in two 12-week clinical trials in patients whose 356 diagnoses corresponded to the DSM-IV category of panic disorder (see CLINICAL TRIALS). 357 Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a 358 discrete period of intense fear or discomfort in which 4 or more of the following symptoms 359 develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or 360 accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath 361 or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal 362 distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear of 363 dying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes. 364 The effectiveness of Prozac in long-term use, i.e., for more than 12 weeks, has not been 365 established in placebo-controlled trials. Therefore, the physician who elects to use Prozac for 366 extended periods should periodically reevaluate the long-term usefulness of the drug for the 367 individual patient (see DOSAGE AND ADMINISTRATION). 368 CONTRAINDICATIONS 369 Prozac is contraindicated in patients known to be hypersensitive to it. 370 Monoamine oxidase inhibitors — There have been reports of serious, sometimes fatal, 371 reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid 372 fluctuations of vital signs, and mental status changes that include extreme agitation progressing 373 to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase 374 inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started 375 on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. 376 Therefore, Prozac should not be used in combination with an MAOI, or within a minimum of 14 377 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have 378 very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has 379 been prescribed chronically and/or at higher doses (see Accumulation and slow elimination 380 under CLINICAL PHARMACOLOGY)] should be allowed after stopping Prozac before starting 381 an MAOI. 382 Pimozide — Concomitant use in patients taking pimozide is contraindicated (see 383 PRECAUTIONS). 384 Thioridazine — Thioridazine should not be administered with Prozac or within a minimum of 385 5 weeks after Prozac has been discontinued (see WARNINGS). 386 WARNINGS 387 Clinical Worsening and Suicide Risk — Patients with major depressive disorder (MDD), 388 both adult and pediatric, may experience worsening of their depression and/or the emergence of 389 suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they 390 are taking antidepressant medications, and this risk may persist until significant remission 391 occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these 392 disorders themselves are the strongest predictors of suicide. There has been a long-standing 393 concern, however, that antidepressants may have a role in inducing worsening of depression and 394 the emergence of suicidality in certain patients during the early phases of treatment. Pooled 395 analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 396 showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in 397 children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and 398 other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality 399 with antidepressants compared to placebo in adults beyond age 24; there was a reduction with 400 antidepressants compared to placebo in adults aged 65 and older. 401 The pooled analyses of placebo-controlled trials in children and adolescents with MDD, 402 obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 403 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of 404 placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 405 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 406 patients. There was considerable variation in risk of suicidality among drugs, but a tendency 407 toward an increase in the younger patients for almost all drugs studied. There were differences in 408 absolute risk of suicidality across the different indications, with the highest incidence in MDD. 409 The risk differences (drug versus placebo), however, were relatively stable within age strata and 410 across indications. These risk differences (drug-placebo difference in the number of cases of 411 suicidality per 1000 patients treated) are provided in Table 1. 412 413 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 414 415 No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but 416 the number was not sufficient to reach any conclusion about drug effect on suicide. 417 It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several 418 months. However, there is substantial evidence from placebo-controlled maintenance trials in 419 adults with depression that the use of antidepressants can delay the recurrence of depression. 420 All patients being treated with antidepressants for any indication should be monitored 421 appropriately and observed closely for clinical worsening, suicidality, and unusual changes 422 in behavior, especially during the initial few months of a course of drug therapy, or at times 423 of dose changes, either increases or decreases. 424 The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, 425 aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have 426 been reported in adult and pediatric patients being treated with antidepressants for major 427 depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. 428 Although a causal link between the emergence of such symptoms and either the worsening of 429 depression and/or the emergence of suicidal impulses has not been established, there is concern 430 that such symptoms may represent precursors to emerging suicidality. 431 Consideration should be given to changing the therapeutic regimen, including possibly 432 discontinuing the medication, in patients whose depression is persistently worse, or who are This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 433 experiencing emergent suicidality or symptoms that might be precursors to worsening depression 434 or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the 435 patient’s presenting symptoms. 436 If the decision has been made to discontinue treatment, medication should be tapered, as 437 rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with 438 certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, 439 Discontinuation of Treatment with Prozac, for a description of the risks of discontinuation of 440 Prozac). 441 Families and caregivers of patients being treated with antidepressants for major 442 depressive disorder or other indications, both psychiatric and nonpsychiatric, should be 443 alerted about the need to monitor patients for the emergence of agitation, irritability, 444 unusual changes in behavior, and the other symptoms described above, as well as the 445 emergence of suicidality, and to report such symptoms immediately to health care 446 providers. Such monitoring should include daily observation by families and caregivers. 447 Prescriptions for Prozac should be written for the smallest quantity of capsules, or liquid 448 consistent with good patient management, in order to reduce the risk of overdose. 449 It should be noted that Prozac is approved in the pediatric population only for major depressive 450 disorder and obsessive compulsive disorder. 451 Screening Patients for Bipolar Disorder — A major depressive episode may be the initial 452 presentation of bipolar disorder. It is generally believed (though not established in controlled 453 trials) that treating such an episode with an antidepressant alone may increase the likelihood of 454 precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the 455 symptoms described above represent such a conversion is unknown. However, prior to initiating 456 treatment with an antidepressant, patients with depressive symptoms should be adequately 457 screened to determine if they are at risk for bipolar disorder; such screening should include a 458 detailed psychiatric history, including a family history of suicide, bipolar disorder, and 459 depression. It should be noted that Prozac is not approved for use in treating bipolar depression. 460 Rash and Possibly Allergic Events — In US fluoxetine clinical trials as of May 8, 1995, 7% 461 of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash 462 and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from 463 treatment because of the rash and/or systemic signs or symptoms associated with the rash. 464 Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, 465 edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild 466 transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine 467 and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these 468 events were reported to recover completely. 469 In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous 470 systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to 471 have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was 472 considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic 473 syndromes suggestive of serum sickness. 474 Since the introduction of Prozac, systemic events, possibly related to vasculitis and including 475 lupus-like syndrome, have developed in patients with rash. Although these events are rare, they 476 may be serious, involving the lung, kidney, or liver. Death has been reported to occur in 477 association with these systemic events. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 478 Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria 479 alone and in combination, have been reported. 480 Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, 481 have been reported rarely. These events have occurred with dyspnea as the only preceding 482 symptom. 483 Whether these systemic events and rash have a common underlying cause or are due to 484 different etiologies or pathogenic processes is not known. Furthermore, a specific underlying 485 immunologic basis for these events has not been identified. Upon the appearance of rash or of 486 other possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac 487 should be discontinued. 488 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions — The 489 development of a potentially life-threatening serotonin syndrome, or Neuroleptic Malignant 490 Syndrome (NMS)-like reactions, has been reported with SNRIs and SSRIs alone, including 491 Prozac treatment, but particularly with concomitant use of serotonergic drugs (including triptans) 492 with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or 493 other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes 494 (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood 495 pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or 496 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).Serotonin syndrome, in its most 497 severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, 498 muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental 499 status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS 500 like signs and symptoms. 501 The concomitant use of Prozac with MAOIs intended to treat depression is contraindicated (see 502 CONTRAINDICATIONS and Drug Interactions under PRECAUTIONS). 503 If concomitant treatment Prozac with a 5-hydroxytryptamine receptor agonist (triptan) is 504 clinically warranted, careful observation of the patient is advised, particularly during treatment 505 initiation and dose increases (see Drug Interactions under PRECAUTIONS). 506 The concomitant use of Prozac with serotonin precursors (such as tryptophan) is not 507 recommended (see Drug Interactions under PRECAUTIONS). 508 Treatment with fluoxetine and any concomitant serotonergic or antidopaminergic agents, 509 including antipsychotics, should be discontinued immediately if the above events occur and 510 supportive symptomatic treatment should be initiated. 511 Potential Interaction with Thioridazine — In a study of 19 healthy male subjects, which 512 included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of 513 thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the 514 slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin 515 hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study 516 suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will 517 produce elevated plasma levels of thioridazine (see PRECAUTIONS). 518 Thioridazine administration produces a dose-related prolongation of the QTc interval, which is 519 associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, 520 and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of 521 thioridazine metabolism (see CONTRAINDICATIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 522 PRECAUTIONS 523 General 524 Abnormal Bleeding — SSRIs and SNRIs, including fluoxetine, may increase the risk of 525 bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and 526 other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control 527 and cohort design) have demonstrated an association between use of drugs that interfere with 528 serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to 529 SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to 530 life-threatening hemorrhages. 531 Patients should be cautioned about the risk of bleeding associated with the concomitant use of 532 fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation (see Drug Interactions). 533 Anxiety and Insomnia — In US placebo-controlled clinical trials for major depressive 534 disorder, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with 535 placebo reported anxiety, nervousness, or insomnia. 536 In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients 537 treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of 538 patients treated with Prozac and in 7% of patients treated with placebo. 539 In US placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of 540 patients treated with Prozac 60 mg, and 13% of patients treated with placebo. Anxiety and 541 nervousness were reported, respectively, in 15% and 11% of patients treated with Prozac 60 mg 542 and in 9% and 5% of patients treated with placebo. 543 Among the most common adverse events associated with discontinuation (incidence at least 544 twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event 545 associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety 546 (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% 547 in major depressive disorder) (see Table 4). 548 Altered Appetite and Weight — Significant weight loss, especially in underweight depressed 549 or bulimic patients may be an undesirable result of treatment with Prozac. 550 In US placebo-controlled clinical trials for major depressive disorder, 11% of patients treated 551 with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). 552 Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated 553 with placebo. However, only rarely have patients discontinued treatment with Prozac because of 554 anorexia or weight loss (see also Pediatric Use under PRECAUTIONS). 555 In US placebo-controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% 556 of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued 557 treatment with Prozac because of anorexia (see also Pediatric Use under PRECAUTIONS). 558 In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac 559 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients 560 treated with Prozac 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients 561 treated with placebo in the 16-week double-blind trial. Weight change should be monitored 562 during therapy. 563 Activation of Mania/Hypomania — In US placebo-controlled clinical trials for major 564 depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Prozac and 565 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a 566 small proportion of patients with Major Affective Disorder treated with other marketed drugs This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 567 effective in the treatment of major depressive disorder (see also Pediatric Use under 568 PRECAUTIONS). 569 In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of 570 patients treated with Prozac and no patients treated with placebo. No patients reported 571 mania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinical 572 trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see also Pediatric 573 Use under PRECAUTIONS). 574 Hyponatremia — Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, 575 including Prozac. In many cases, this hyponatremia appears to be the result of the syndrome of 576 inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 577 110 mmol/L have been reported and appeared to be reversible when Prozac was discontinued. 578 Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, 579 patients taking diuretics or who are otherwise volume depleted may be at greater risk (see 580 Geriatric Use). Discontinuation of Prozac should be considered in patients with symptomatic 581 hyponatremia and appropriate medical intervention should be instituted. 582 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory 583 impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or 584 acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, 585 and death. 586 Seizures — In US placebo-controlled clinical trials for major depressive disorder, convulsions 587 (or events described as possibly having been seizures) were reported in 0.1% of patients treated 588 with Prozac and 0.2% of patients treated with placebo. No patients reported convulsions in US 589 placebo-controlled clinical trials for either OCD or bulimia. In all US Prozac clinical trials as of 590 May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar 591 to that associated with other marketed drugs effective in the treatment of major depressive 592 disorder. Prozac should be introduced with care in patients with a history of seizures. 593 The Long Elimination Half-Lives of Fluoxetine and its Metabolites — Because of the long 594 elimination half-lives of the parent drug and its major active metabolite, changes in dose will not 595 be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose 596 and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND 597 ADMINISTRATION). 598 Use in Patients with Concomitant Illness — Clinical experience with Prozac in patients with 599 concomitant systemic illness is limited. Caution is advisable in using Prozac in patients with 600 diseases or conditions that could affect metabolism or hemodynamic responses. 601 Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent 602 history of myocardial infarction or unstable heart disease. Patients with these diagnoses were 603 systematically excluded from clinical studies during the product’s premarket testing. However, 604 the electrocardiograms of 312 patients who received Prozac in double-blind trials were 605 retrospectively evaluated; no conduction abnormalities that resulted in heart block were 606 observed. The mean heart rate was reduced by approximately 3 beats/min. 607 In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, 608 norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A 609 lower or less frequent dose should be used in patients with cirrhosis. 610 Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or 611 norfluoxetine in plasma (see Renal disease under CLINICAL PHARMACOLOGY). Use of a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 612 lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE 613 AND ADMINISTRATION). 614 In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred 615 during therapy with Prozac, and hyperglycemia has developed following discontinuation of the 616 drug. As is true with many other types of medication when taken concurrently by patients with 617 diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with 618 Prozac is instituted or discontinued. 619 Interference with Cognitive and Motor Performance — Any psychoactive drug may impair 620 judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous 621 machinery, including automobiles, until they are reasonably certain that the drug treatment does 622 not affect them adversely. 623 Discontinuation of Treatment with Prozac — During marketing of Prozac and other SSRIs 624 and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous 625 reports of adverse events occurring upon discontinuation of these drugs, particularly when 626 abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory 627 disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, 628 lethargy, emotional lability, insomnia, and hypomania. While these events are generally 629 self-limiting, there have been reports of serious discontinuation symptoms. Patients should be 630 monitored for these symptoms when discontinuing treatment with Prozac. A gradual reduction in 631 the dose rather than abrupt cessation is recommended whenever possible. If intolerable 632 symptoms occur following a decrease in the dose or upon discontinuation of treatment, then 633 resuming the previously prescribed dose may be considered. Subsequently, the physician may 634 continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine 635 concentration decrease gradually at the conclusion of therapy, which may minimize the risk of 636 discontinuation symptoms with this drug (see DOSAGE AND ADMINISTRATION). 637 Information for Patients 638 Prescribers or other health professionals should inform patients, their families, and their 639 caregivers about the benefits and risks associated with treatment with Prozac and should counsel 640 them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, 641 Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available 642 for Prozac. The prescriber or health professional should instruct patients, their families, and their 643 caregivers to read the Medication Guide and should assist them in understanding its contents. 644 Patients should be given the opportunity to discuss the contents of the Medication Guide and to 645 obtain answers to any questions they may have. The complete text of the Medication Guide is 646 reprinted at the end of this document. 647 Patients should be advised of the following issues and asked to alert their prescriber if these 648 occur while taking Prozac. 649 Clinical Worsening and Suicide Risk — Patients, their families, and their caregivers should 650 be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, 651 irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), 652 hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal 653 ideation, especially early during antidepressant treatment and when the dose is adjusted up or 654 down. Families and caregivers of patients should be advised to look for the emergence of such 655 symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be 656 reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in 657 onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 658 associated with an increased risk for suicidal thinking and behavior and indicate a need for very 659 close monitoring and possibly changes in the medication. 660 Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome 661 with the concomitant use of Prozac and triptans, tramadol or other serotonergic agents. 662 Because Prozac may impair judgment, thinking, or motor skills, patients should be advised to 663 avoid driving a car or operating hazardous machinery until they are reasonably certain that their 664 performance is not affected. 665 Patients should be advised to inform their physician if they are taking or plan to take any 666 prescription or over-the-counter drugs, or alcohol. 667 Abnormal Bleeding— Patients should be cautioned about the concomitant use of fluoxetine 668 and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of 669 psychotropic drugs that interfere with serotonin reuptake and these agents have been associated 670 with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). 671 Patients should be advised to notify their physician if they become pregnant or intend to 672 become pregnant during therapy. 673 Patients should be advised to notify their physician if they are breast-feeding an infant. 674 Patients should be advised to notify their physician if they develop a rash or hives. 675 Laboratory Tests 676 There are no specific laboratory tests recommended. 677 Drug Interactions 678 As with all drugs, the potential for interaction by a variety of mechanisms (e.g., 679 pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see 680 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). 681 Drugs metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make 682 individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. 683 Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including 684 certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), 685 and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with 686 caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system 687 and that have a relatively narrow therapeutic index (see list below) should be initiated at the low 688 end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the 689 previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If 690 fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by 691 CYP2D6, the need for decreased dose of the original medication should be considered. Drugs 692 with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, 693 vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death 694 potentially associated with elevated plasma levels of thioridazine, thioridazine should not be 695 administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been 696 discontinued (see CONTRAINDICATIONS and WARNINGS). 697 Drugs metabolized by CYP3A4 — In an in vivo interaction study involving coadministration 698 of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma 699 terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies 700 have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more 701 potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for 702 this enzyme, including astemizole, cisapride, and midazolam. These data indicate that 703 fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 704 CNS active drugs — The risk of using Prozac in combination with other CNS active drugs has 705 not been systematically evaluated. Nonetheless, caution is advised if the concomitant 706 administration of Prozac and such drugs is required. In evaluating individual cases, consideration 707 should be given to using lower initial doses of the concomitantly administered drugs, using 708 conservative titration schedules, and monitoring of clinical status (see Accumulation and slow 709 elimination under CLINICAL PHARMACOLOGY). 710 Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed 711 elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following 712 initiation of concomitant fluoxetine treatment. 713 Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or 714 pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of 715 haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. 716 Clinical studies of pimozide with other antidepressants demonstrate an increase in drug 717 interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not 718 been conducted, the potential for drug interactions or QTc prolongation warrants restricting the 719 concurrent use of pimozide and Prozac. Concomitant use of Prozac and pimozide is 720 contraindicated (see CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS 721 and WARNINGS. 722 Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in 723 some patients (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). 724 Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma 725 concentrations and in further psychomotor performance decrement due to increased alprazolam 726 levels. 727 Lithium — There have been reports of both increased and decreased lithium levels when 728 lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased 729 serotonergic effects have been reported. Lithium levels should be monitored when these drugs 730 are administered concomitantly. 731 Tryptophan — Five patients receiving Prozac in combination with tryptophan experienced 732 adverse reactions, including agitation, restlessness, and gastrointestinal distress. 733 Monoamine oxidase inhibitors — See CONTRAINDICATIONS. 734 Other drugs effective in the treatment of major depressive disorder — In 2 studies, previously 735 stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold 736 when fluoxetine has been administered in combination. This influence may persist for 3 weeks or 737 longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and 738 plasma TCA concentrations may need to be monitored temporarily when fluoxetine is 739 coadministered or has been recently discontinued (see Accumulation and slow elimination under 740 CLINICAL PHARMACOLOGY, and Drugs metabolized by CYP2D6 under Drug Interactions). 741 Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including 742 Prozac, and the potential for serotonin syndrome, caution is advised when Prozac is 743 coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such 744 as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, 745 or St. John’s Wort (see Serotonin Syndrome under WARNINGS). The concomitant use of 746 Prozac with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). 747 Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an 748 SSRI and a triptan. If concomitant treatment of Prozac with a triptan is clinically warranted, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 749 careful observation of the patient is advised, particularly during treatment initiation and dose 750 increases (see Serotonin Syndrome under WARNINGS). 751 Potential effects of coadministration of drugs tightly bound to plasma proteins — Because 752 fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking 753 another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in 754 plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may 755 result from displacement of protein-bound fluoxetine by other tightly-bound drugs (see 756 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). 757 Drugs that interfere with hemostasis (e.g., NSAIDs, Aspirin, Warfarin) — Serotonin release by 758 platelets plays an important role in hemostasis. Epidemiological studies of the case-control and 759 cohort design that have demonstrated an association between use of psychotropic drugs that 760 interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also 761 shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered 762 anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs 763 are coadministered with warfarin. Patients receiving warfarin therapy should be carefully 764 monitored when fluoxetine is initiated or discontinued. 765 Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the 766 combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in 767 patients on fluoxetine receiving ECT treatment. 768 Carcinogenesis, Mutagenesis, Impairment of Fertility 769 There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. 770 Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times 771 the MRHD on a mg/m2 basis) was not observed. 772 Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at 773 doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, 774 the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no 775 evidence of carcinogenicity. 776 Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects 777 based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat 778 hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese 779 hamster bone marrow cells. 780 Impairment of fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 781 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that 782 fluoxetine had no adverse effects on fertility (see Pediatric Use). 783 Pregnancy 784 Pregnancy Category C — In embryo-fetal development studies in rats and rabbits, there was 785 no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, 786 respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m2 basis) throughout 787 organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in 788 pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following 789 maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 790 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was 791 no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 792 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 793 times the MRHD on a mg/m2 basis). Prozac should be used during pregnancy only if the 794 potential benefit justifies the potential risk to the fetus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 795 Nonteratogenic Effects — Neonates exposed to Prozac and other SSRIs or serotonin and 796 norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed 797 complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such 798 complications can arise immediately upon delivery. Reported clinical findings have included 799 respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, 800 vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and 801 constant crying. These features are consistent with either a direct toxic effect of SSRIs and 802 SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the 803 clinical picture is consistent with serotonin syndrome (see Monoamine oxidase inhibitors under 804 CONTRAINDICATIONS). 805 Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent 806 pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the 807 general population and is associated with substantial neonatal morbidity and mortality. In a 808 retrospective case-control study of 377 women whose infants were born with PPHN and 836 809 women whose infants were born healthy, the risk for developing PPHN was approximately 810 six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants 811 who had not been exposed to antidepressants during pregnancy. There is currently no 812 corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; 813 this is the first study that has investigated the potential risk. The study did not include enough 814 cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN 815 risk. 816 When treating a pregnant woman with Prozac during the third trimester, the physician should 817 carefully consider both the potential risks and benefits of treatment (see DOSAGE AND 818 ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 819 women with a history of major depression who were euthymic at the beginning of pregnancy, 820 women who discontinued antidepressant medication during pregnancy were more likely to 821 experience a relapse of major depression than women who continued antidepressant medication. 822 Labor and Delivery 823 The effect of Prozac on labor and delivery in humans is unknown. However, because 824 fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse 825 effects on the newborn, fluoxetine should be used during labor and delivery only if the potential 826 benefit justifies the potential risk to the fetus. 827 Nursing Mothers 828 Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In 829 one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The 830 concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were 831 reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep 832 disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of 833 fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. 834 Pediatric Use 835 The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 836 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 (see 837 CLINICAL TRIALS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 838 The efficacy of Prozac for the treatment of OCD was demonstrated in one 13-week 839 placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 (see CLINICAL 840 TRIALS). 841 The safety and effectiveness in pediatric patients <8 years of age in major depressive disorder 842 and <7 years of age in OCD have not been established. 843 Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major 844 depressive disorder or OCD (see Pharmacokinetics under CLINICAL PHARMACOLOGY). 845 The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 846 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies 847 with fluoxetine. The longer-term adverse event profile observed in the 19-week major depressive 848 disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar 849 to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS). 850 Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out 851 of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. 852 Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the 853 acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of 854 mania/hypomania is recommended. 855 As with other SSRIs, decreased weight gain has been observed in association with the use of 856 fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, 857 pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) 858 and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine 859 treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine 860 treatment for pediatric patients has not been systematically assessed for chronic treatment longer 861 than several months in duration. In particular, there are no studies that directly evaluate the 862 longer-term effects of fluoxetine on the growth, development, and maturation of children and 863 adolescent patients. Therefore, height and weight should be monitored periodically in pediatric 864 patients receiving fluoxetine. 865 (See WARNINGS, Clinical Worsening and Suicide Risk.) 866 Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive 867 toxicity, and impaired bone development, has been observed following exposure of juvenile 868 animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. 869 In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from 870 weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development 871 was delayed at all doses, and growth (body weight gain, femur length) was decreased during the 872 dosing period in animals receiving the highest dose. At the end of the treatment period, serum 873 levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high 874 doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle 875 degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and 876 hypospermia) was observed at the high dose. When animals were evaluated after a recovery 877 period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased 878 reactivity at all doses and learning deficit at the high dose) and reproductive functional 879 impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in 880 addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were 881 found in the high dose group, indicating that the reproductive organ effects seen at the end of 882 treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not 883 assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 884 juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma 885 exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in 886 this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in 887 pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat 888 exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 889 times, respectively, pediatric exposure at the MRD. 890 A specific effect of fluoxetine on bone development has been reported in mice treated with 891 fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, 892 intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in 893 decreased bone mineral content and density. These doses did not affect overall growth (body 894 weight gain or femoral length). The doses administered to juvenile mice in this study are 895 approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) 896 basis. 897 In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early 898 postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors 899 (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in 900 adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric 901 MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of 902 these findings to the approved pediatric use in humans is uncertain. 903 Prozac is approved for use in pediatric patients with MDD and OCD (see BOX WARNING 904 and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Prozac 905 in a child or adolescent must balance the potential risks with the clinical need. 906 Geriatric Use 907 US fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years 908 of age. The efficacy in geriatric patients has been established (see CLINICAL TRIALS). For 909 pharmacokinetic information in geriatric patients, see Age under CLINICAL 910 PHARMACOLOGY. No overall differences in safety or effectiveness were observed between 911 these subjects and younger subjects, and other reported clinical experience has not identified 912 differences in responses between the elderly and younger patients, but greater sensitivity of some 913 older individuals cannot be ruled out. SSRIs and SNRIs, including Prozac, have been associated 914 with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk 915 for this adverse event (see PRECAUTIONS, Hyponatremia). 916 ADVERSE REACTIONS 917 Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in 918 US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered 919 Prozac in panic clinical trials. Adverse events were recorded by clinical investigators using 920 descriptive terminology of their own choosing. Consequently, it is not possible to provide a 921 meaningful estimate of the proportion of individuals experiencing adverse events without first 922 grouping similar types of events into a limited (i.e., reduced) number of standardized event 923 categories. 924 In the tables and tabulations that follow, COSTART Dictionary terminology has been used to 925 classify reported adverse events. The stated frequencies represent the proportion of individuals 926 who experienced, at least once, a treatment-emergent adverse event of the type listed. An event 927 was considered treatment-emergent if it occurred for the first time or worsened while receiving 928 therapy following baseline evaluation. It is important to emphasize that events reported during 929 therapy were not necessarily caused by it. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 930 The prescriber should be aware that the figures in the tables and tabulations cannot be used to 931 predict the incidence of side effects in the course of usual medical practice where patient 932 characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, 933 the cited frequencies cannot be compared with figures obtained from other clinical investigations 934 involving different treatments, uses, and investigators. The cited figures, however, do provide the 935 prescribing physician with some basis for estimating the relative contribution of drug and 936 nondrug factors to the side effect incidence rate in the population studied. 937 Incidence in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled 938 clinical trials (excluding data from extensions of trials) — Table 2 enumerates the most common 939 treatment-emergent adverse events associated with the use of Prozac (incidence of at least 5% for 940 Prozac and at least twice that for placebo within at least 1 of the indications) for the treatment of 941 major depressive disorder, OCD, and bulimia in US controlled clinical trials and panic disorder 942 in US plus non-US controlled trials. Table 3 enumerates treatment-emergent adverse events that 943 occurred in 2% or more patients treated with Prozac and with incidence greater than placebo who 944 participated in US major depressive disorder, OCD, and bulimia controlled clinical trials and US 945 plus non-US panic disorder controlled clinical trials. Table 3 provides combined data for the pool 946 of studies that are provided separately by indication in Table 2. 947 948 Table 2: Most Common Treatment-Emergent Adverse Events: Incidence in Major 949 Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical 950 Trials1 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Event Prozac (N=1728) Placebo (N=975) Prozac (N=266) Placebo (N=89) Prozac (N=450) Placebo (N=267) Prozac (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence2 2 -- -- -- 7 -- 1 -- Abnormal ejaculation2 -- -- 7 -- 7 -- 2 1 951 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US 952 data for panic disorder clinical trials. 953 2 Denominator used was for males only (N=690 Prozac major depressive disorder; N=410 placebo major 954 depressive disorder; N=116 Prozac OCD; N=43 placebo OCD; N=14 Prozac bulimia; N=1 placebo bulimia; 955 N=162 Prozac panic; N=121 placebo panic). 956 -- Incidence less than 1%. 957 958 Table 3: Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, 959 OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Event2 Prozac (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 960 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US 961 data for panic disorder clinical trials. 962 2 Included are events reported by at least 2% of patients taking Prozac, except the following events, which had an 963 incidence on placebo ≥ Prozac (major depressive disorder, OCD, bulimia, and panic disorder combined): 964 abdominal pain, abnormal dreams, accidental injury, back pain, cough increased, major depressive disorder 965 (includes suicidal thoughts), dysmenorrhea, infection, myalgia, pain, paresthesia, pharyngitis, rhinitis, sinusitis. 966 -- Incidence less than 1%. 967 968 Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic 969 disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 4 970 lists the adverse events associated with discontinuation of Prozac treatment (incidence at least 971 twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event 972 associated with discontinuation) in major depressive disorder, OCD, bulimia, and panic disorder 973 clinical trials, plus non-US panic disorder clinical trials. 974 975 Table 4: Most Common Adverse Events Associated with Discontinuation in Major 976 Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical 977 Trials1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) -- -- Rash (1%) -- -- 978 1 Includes US major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic 979 disorder clinical trials. 980 981 Other adverse events in pediatric patients (children and adolescents) — Treatment-emergent 982 adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142 983 placebo-treated). The overall profile of adverse events was generally similar to that seen in adult 984 studies, as shown in Tables 2 and 3. However, the following adverse events (excluding those 985 which appear in the body or footnotes of Tables 2 and 3 and those for which the COSTART 986 terms were uninformative or misleading) were reported at an incidence of at least 2% for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 987 fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, 988 epistaxis, urinary frequency, and menorrhagia. 989 The most common adverse event (incidence at least 1% for fluoxetine and greater than 990 placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 991 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for 992 fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary event 993 associated with discontinuation was collected. 994 Events observed in Prozac Weekly clinical trials — Treatment-emergent adverse events in 995 clinical trials with Prozac Weekly were similar to the adverse events reported by patients in 996 clinical trials with Prozac daily. In a placebo-controlled clinical trial, more patients taking Prozac 997 Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking 998 Prozac 20 mg daily (10% versus 5%, respectively). 999 Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual 1000 performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they 1001 may also be a consequence of pharmacologic treatment. In particular, some evidence suggests 1002 that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and 1003 severity of untoward experiences involving sexual desire, performance, and satisfaction are 1004 difficult to obtain, however, in part because patients and physicians may be reluctant to discuss 1005 them. Accordingly, estimates of the incidence of untoward sexual experience and performance, 1006 cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in 1007 US major depressive disorder, OCD, and bulimia placebo-controlled clinical trials, decreased 1008 libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% 1009 fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of 1010 orgasmic dysfunction, including anorgasmia. 1011 There are no adequate and well-controlled studies examining sexual dysfunction with 1012 fluoxetine treatment. 1013 Priapism has been reported with all SSRIs. 1014 While it is difficult to know the precise risk of sexual dysfunction associated with the use of 1015 SSRIs, physicians should routinely inquire about such possible side effects. 1016 Other Events Observed in Clinical Trials 1017 Following is a list of all treatment-emergent adverse events reported at anytime by individuals 1018 taking fluoxetine in US clinical trials as of May 8, 1995 (10,782 patients) except (1) those listed 1019 in the body or footnotes of Tables 2 or 3 above or elsewhere in labeling; (2) those for which the 1020 COSTART terms were uninformative or misleading; (3) those events for which a causal 1021 relationship to Prozac use was considered remote; and (4) events occurring in only 1 patient 1022 treated with Prozac and which did not have a substantial probability of being acutely 1023 life-threatening. 1024 Events are classified within body system categories using the following definitions: frequent 1025 adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; 1026 infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those 1027 occurring in less than 1/1000 patients. 1028 Body as a Whole — Frequent: chest pain, chills; Infrequent: chills and fever, face edema, 1029 intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, 1030 hypothermia, intentional injury, neuroleptic malignant syndrome1, photosensitivity reaction. 1031 Cardiovascular System — Frequent: hemorrhage, hypertension, palpitation; Infrequent: 1032 angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 1033 postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, 1034 bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart 1035 arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, 1036 thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. 1037 Digestive System — Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous 1038 stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, 1039 glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, 1040 melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: 1041 biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal 1042 incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, 1043 intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary 1044 gland enlargement, stomach ulcer hemorrhage, tongue edema. 1045 Endocrine System — Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. 1046 Hemic and Lymphatic System — Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, 1047 hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, 1048 thrombocythemia, thrombocytopenia. 1049 Metabolic and Nutritional — Frequent: weight gain; Infrequent: dehydration, generalized 1050 edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol 1051 intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, 1052 hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. 1053 Musculoskeletal System — Infrequent: arthritis, bone pain, bursitis, leg cramps, 1054 tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, 1055 osteomyelitis, osteoporosis, rheumatoid arthritis. 1056 Nervous System — Frequent: agitation, amnesia, confusion, emotional lability, sleep 1057 disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal 1058 syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, 1059 hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, 1060 neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder2, psychosis, vertigo; 1061 Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, 1062 delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, 1063 paralysis, reflexes decreased, reflexes increased, stupor. 1064 Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, 1065 atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, 1066 lung edema, pneumothorax, stridor. 1067 Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, eczema, 1068 maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, 1069 herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. 1070 Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry 1071 eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye 1072 hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field 1073 defect. 1074 Urogenital System — Frequent: urinary frequency; Infrequent: abortion3, albuminuria, 1075 amenorrhea3, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation3, 1076 fibrocystic breast3, hematuria, leukorrhea3, menorrhagia3, metrorrhagia3, nocturia, polyuria, 1077 urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage3; Rare: breast This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 1078 engorgement, glycosuria, hypomenorrhea3, kidney pain, oliguria, priapism3, uterine 1079 hemorrhage3, uterine fibroids enlarged3. 1080 1 Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome. 1081 2 Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. 1082 3 Adjusted for gender. 1083 1084 Postintroduction Reports 1085 Voluntary reports of adverse events temporally associated with Prozac that have been received 1086 since market introduction and that may have no causal relationship with the drug include the 1087 following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic 1088 jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory 1089 syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 1090 weeks of fluoxetine therapy and which completely resolved over the next few months following 1091 drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, 1092 erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, 1093 hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, 1094 misuse/abuse, movement disorders developing in patients with risk factors including drugs 1095 associated with such events and worsening of preexisting movement disorders, optic neuritis, 1096 pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT 1097 prolongation, Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, 1098 thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, 1099 ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors. 1100 DRUG ABUSE AND DEPENDENCE 1101 Controlled substance class — Prozac is not a controlled substance. 1102 Physical and psychological dependence — Prozac has not been systematically studied, in 1103 animals or humans, for its potential for abuse, tolerance, or physical dependence. While the 1104 premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal 1105 syndrome or any drug seeking behavior, these observations were not systematic and it is not 1106 possible to predict on the basis of this limited experience the extent to which a CNS active drug 1107 will be misused, diverted, and/or abused once marketed. Consequently, physicians should 1108 carefully evaluate patients for history of drug abuse and follow such patients closely, observing 1109 them for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation of 1110 dose, drug-seeking behavior). 1111 OVERDOSAGE 1112 Human Experience 1113 Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients 1114 (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with 1115 other drugs, reported from this population, there were 195 deaths. 1116 Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a 1117 fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, 1118 including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, 1119 pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, 1120 and hypomania. The remaining 206 patients had an unknown outcome. The most common signs 1121 and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, 1122 tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 1123 patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. 1124 However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been 1125 associated with lethal outcome, but causality has not been established. 1126 Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose 1127 involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients 1128 completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown 1129 outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s 1130 syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 1131 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and 1132 promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in 1133 children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which 1134 was nonlethal. 1135 Other important adverse events reported with fluoxetine overdose (single or multiple drugs) 1136 include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular 1137 tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic 1138 malignant syndrome-like events, pyrexia, stupor, and syncope. 1139 Animal Experience 1140 Studies in animals do not provide precise or necessarily valid information about the treatment 1141 of human overdose. However, animal experiments can provide useful insights into possible 1142 treatment strategies. 1143 The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. 1144 Acute high oral doses produced hyperirritability and convulsions in several animal species. 1145 Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. 1146 Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary 1147 dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure 1148 occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, 1149 chronically. 1150 In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation 1151 of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. 1152 Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the 1153 ECG should ordinarily be monitored in cases of human overdose (see Management of 1154 Overdose). 1155 Management of Overdose 1156 Treatment should consist of those general measures employed in the management of 1157 overdosage with any drug effective in the treatment of major depressive disorder. 1158 Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital 1159 signs. General supportive and symptomatic measures are also recommended. Induction of emesis 1160 is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway 1161 protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic 1162 patients. 1163 Activated charcoal should be administered. Due to the large volume of distribution of this 1164 drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of 1165 benefit. No specific antidotes for fluoxetine are known. 1166 A specific caution involves patients who are taking or have recently taken fluoxetine and might 1167 ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or 1168 an active metabolite may increase the possibility of clinically significant sequelae and extend the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 1169 time needed for close medical observation (see Other drugs effective in the treatment of major 1170 depressive disorder under PRECAUTIONS). 1171 Based on experience in animals, which may not be relevant to humans, fluoxetine-induced 1172 seizures that fail to remit spontaneously may respond to diazepam. 1173 In managing overdosage, consider the possibility of multiple drug involvement. The physician 1174 should consider contacting a poison control center for additional information on the treatment of 1175 any overdose. Telephone numbers for certified poison control centers are listed in the 1176 Physicians’ Desk Reference (PDR). 1177 DOSAGE AND ADMINISTRATION 1178 Major Depressive Disorder 1179 Initial Treatment 1180 Adult — In controlled trials used to support the efficacy of fluoxetine, patients were 1181 administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, 1182 and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response 1183 in major depressive disorder in most cases. Consequently, a dose of 20 mg/day, administered in 1184 the morning, is recommended as the initial dose. 1185 A dose increase may be considered after several weeks if insufficient clinical improvement is 1186 observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID 1187 schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. 1188 Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials 1189 of fluoxetine supporting its effectiveness in the treatment of major depressive disorder, patients 1190 were administered fluoxetine doses of 10 to 20 mg/day (see CLINICAL TRIALS). Treatment 1191 should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should 1192 be increased to 20 mg/day. 1193 However, due to higher plasma levels in lower weight children, the starting and target dose in 1194 this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several 1195 weeks if insufficient clinical improvement is observed. 1196 All patients — As with other drugs effective in the treatment of major depressive disorder, the 1197 full effect may be delayed until 4 weeks of treatment or longer. 1198 As with many other medications, a lower or less frequent dosage should be used in patients 1199 with hepatic impairment. A lower or less frequent dosage should also be considered for the 1200 elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or 1201 on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely 1202 necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use 1203 in Patients with Concomitant Illness under PRECAUTIONS). 1204 Maintenance/Continuation/Extended Treatment 1205 It is generally agreed that acute episodes of major depressive disorder require several months 1206 or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is 1207 identical to the dose needed to maintain and/or sustain euthymia is unknown. 1208 Daily Dosing 1209 Systematic evaluation of Prozac in adult patients has shown that its efficacy in major 1210 depressive disorder is maintained for periods of up to 38 weeks following 12 weeks of 1211 open-label acute treatment (50 weeks total) at a dose of 20 mg/day (see CLINICAL TRIALS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 1212 Weekly Dosing 1213 Systematic evaluation of Prozac Weekly in adult patients has shown that its efficacy in major 1214 depressive disorder is maintained for periods of up to 25 weeks with once-weekly dosing 1215 following 13 weeks of open-label treatment with Prozac 20 mg once daily. However, therapeutic 1216 equivalence of Prozac Weekly given on a once-weekly basis with Prozac 20 mg given daily for 1217 delaying time to relapse has not been established (see CLINICAL TRIALS). 1218 Weekly dosing with Prozac Weekly capsules is recommended to be initiated 7 days after the 1219 last daily dose of Prozac 20 mg (see Weekly dosing under CLINICAL PHARMACOLOGY). 1220 If satisfactory response is not maintained with Prozac Weekly, consider reestablishing a daily 1221 dosing regimen (see CLINICAL TRIALS). 1222 Switching Patients to a Tricyclic Antidepressant (TCA) 1223 Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be 1224 monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see 1225 Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS, Drug 1226 Interactions). 1227 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) 1228 At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy 1229 with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping 1230 Prozac before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS). 1231 Obsessive Compulsive Disorder 1232 Initial Treatment 1233 Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the 1234 treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine 1235 or placebo (see CLINICAL TRIALS). In 1 of these studies, no dose-response relationship for 1236 effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the 1237 morning, is recommended as the initial dose. Since there was a suggestion of a possible 1238 dose-response relationship for effectiveness in the second study, a dose increase may be 1239 considered after several weeks if insufficient clinical improvement is observed. The full 1240 therapeutic effect may be delayed until 5 weeks of treatment or longer. 1241 Doses above 20 mg/day may be administered on a once-a-day (i.e., morning) or BID schedule 1242 (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of 1243 up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose 1244 should not exceed 80 mg/day. 1245 Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting 1246 its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the 1247 range of 10 to 60 mg/day (see CLINICAL TRIALS). 1248 In adolescents and higher weight children, treatment should be initiated with a dose of 1249 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases 1250 may be considered after several more weeks if insufficient clinical improvement is observed. A 1251 dose range of 20 to 60 mg/day is recommended. 1252 In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional 1253 dose increases may be considered after several more weeks if insufficient clinical improvement 1254 is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses 1255 greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 1256 All patients — As with the use of Prozac in the treatment of major depressive disorder, a lower 1257 or less frequent dosage should be used in patients with hepatic impairment. A lower or less 1258 frequent dosage should also be considered for the elderly (see Geriatric Use under 1259 PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant 1260 medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver 1261 disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with 1262 Concomitant Illness under PRECAUTIONS). 1263 Maintenance/Continuation Treatment 1264 While there are no systematic studies that answer the question of how long to continue Prozac, 1265 OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. 1266 Although the efficacy of Prozac after 13 weeks has not been documented in controlled trials, 1267 adult patients have been continued in therapy under double-blind conditions for up to an 1268 additional 6 months without loss of benefit. However, dosage adjustments should be made to 1269 maintain the patient on the lowest effective dosage, and patients should be periodically 1270 reassessed to determine the need for treatment. 1271 Bulimia Nervosa 1272 Initial Treatment 1273 In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of 1274 bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or 1275 placebo (see CLINICAL TRIALS). Only the 60-mg dose was statistically significantly superior 1276 to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the 1277 recommended dose is 60 mg/day, administered in the morning. For some patients it may be 1278 advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day 1279 have not been systematically studied in patients with bulimia. 1280 As with the use of Prozac in the treatment of major depressive disorder and OCD, a lower or 1281 less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent 1282 dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and 1283 for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments 1284 for renal impairment are not routinely necessary (see Liver disease and Renal disease under 1285 CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under 1286 PRECAUTIONS). 1287 Maintenance/Continuation Treatment 1288 Systematic evaluation of continuing Prozac 60 mg/day for periods of up to 52 weeks in 1289 patients with bulimia who have responded while taking Prozac 60 mg/day during an 8-week 1290 acute treatment phase has demonstrated a benefit of such maintenance treatment (see CLINICAL 1291 TRIALS). Nevertheless, patients should be periodically reassessed to determine the need for 1292 maintenance treatment. 1293 Panic Disorder 1294 Initial Treatment 1295 In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of 1296 panic disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see 1297 CLINICAL TRIALS). Treatment should be initiated with a dose of 10 mg/day. After 1 week, the 1298 dose should be increased to 20 mg/day. The most frequently administered dose in the 2 1299 flexible-dose clinical trials was 20 mg/day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 1300 A dose increase may be considered after several weeks if no clinical improvement is observed. 1301 Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with panic 1302 disorder. 1303 As with the use of Prozac in other indications, a lower or less frequent dosage should be used 1304 in patients with hepatic impairment. A lower or less frequent dosage should also be considered 1305 for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent 1306 disease or on multiple concomitant medications. Dosage adjustments for renal impairment are 1307 not routinely necessary (see Liver disease and Renal disease under CLINICAL 1308 PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). 1309 Maintenance/Continuation Treatment 1310 While there are no systematic studies that answer the question of how long to continue Prozac, 1311 panic disorder is a chronic condition and it is reasonable to consider continuation for a 1312 responding patient. Nevertheless, patients should be periodically reassessed to determine the 1313 need for continued treatment. 1314 Special Populations 1315 Treatment of Pregnant Women During the Third Trimester 1316 Neonates exposed to Prozac and other SSRIs or SNRIs, late in the third trimester have 1317 developed complications requiring prolonged hospitalization, respiratory support, and tube 1318 feeding (see PRECAUTIONS). When treating pregnant women with Prozac during the third 1319 trimester, the physician should carefully consider the potential risks and benefits of treatment. 1320 The physician may consider tapering Prozac in the third trimester. 1321 Discontinuation of Treatment with Prozac 1322 Symptoms associated with discontinuation of Prozac and other SSRIs and SNRIs, have been 1323 reported (see PRECAUTIONS). Patients should be monitored for these symptoms when 1324 discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is 1325 recommended whenever possible. If intolerable symptoms occur following a decrease in the dose 1326 or upon discontinuation of treatment, then resuming the previously prescribed dose may be 1327 considered. Subsequently, the physician may continue decreasing the dose but at a more gradual 1328 rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of 1329 therapy which may minimize the risk of discontinuation symptoms with this drug. 1330 HOW SUPPLIED 1331 The following products are manufactured by Eli Lilly and Company for Dista Products 1332 Company. 1333 Prozac® Pulvules®, USP, are available in: The 10-mg1, Pulvule is opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body: NDC 0777-3104-02 (PU31042) - Bottles of 100 The 20-mg1 Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body: NDC 0777-3105-30 (PU31052) - Bottles of 30 NDC 0777-3105-02 (PU31052) - Bottles of 100 NDC 0777-3105-07 (PU31052) - Bottles of 2000 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 The 40-mg1 Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body: NDC 0777-3107-30 (PU31072) - Bottles of 30 The following is manufactured by OSG Norwich Pharmaceuticals, Inc., North Norwich, NY, 13814, for Dista Products Company: Liquid, Oral Solution is available in: 20 mg1 per 5 mL with mint flavor: NDC 0777-5120-58 (MS-51203) - Bottles of 120 mL The following product is manufactured and distributed by Eli Lilly and Company: Prozac® Weekly™ Capsules are available in: The 90-mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) - Blister package of 4 1334 ______________________ 1335 1 Fluoxetine base equivalent. 1336 2 Protect from light. 1337 3 Dispense in a tight, light-resistant container. 1338 1339 Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). 1340 ANIMAL TOXICOLOGY 1341 Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine 1342 chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid 1343 accumulation in animals has been observed with many cationic amphiphilic drugs, including 1344 fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. 1345 Literature revised MMM DD, 2009 1346 Eli Lilly and Company 1347 Indianapolis, IN 46285, USA 1348 1349 www.lilly.com 1.0 NL PV 5327 DPP PRINTED IN USA 1350 1351 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:06.001980	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018936s088,020101s042,021235s014lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 88}
11,384	Document Information Page This page is for FDA internal use only. Do NOT send this page with the letter. Application #(s): NDA 18-961/S-012 Document Type: Supplement Letter Document Group: Approval Letters Document Name: Approval letter based on enclosed/submitted labeling text Letter Code: SNDA-I1 COMIS Decision: AP: APPROVAL Drafted by: smm/February 19, 2002 Revised by: Smm/April 12, 2002/E.Galliers/04.21.02/ Initialed by: E Galliers 2.19.02 Finalized: E.M.G./04.23.02/ Filename: N1896212.doc DFS Key Words: Notes: SLR to add aluminum content language to package insert and vial label. Linking Instructions: If this is the first action on the application, link the outgoing letter to the initial submission, RS, AR, or FO coded incoming document for the supplement being acted on, as appropriate. Otherwise, the outgoing letter must be linked to the major amendment submitted in response to the previous action letter. In addition, the outgoing document should also be linked to all associated amendments and correspondences included in the action. END OF DOCUMENT INFORMATION PAGE The letter begins on the next page. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville MD 20857 NDA 18-961/S-012 Abbott Laboratories Attention: Jean Kirkeleit Davis Manager, HPD Regulatory Affairs 200 Abbott Park Road, D389, J45 Abbott Park, IL 60064-6157 Dear Ms. Davis: Please refer to your supplemental new drug application dated August 22, 2001, received August 24, 2001, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Chromic Chloride Injection, USP, 4 mcg/mL. We acknowledge receipt of your submission dated February 15, 2002. This supplemental new drug application provides for the addition of an aluminum toxicity statement to the WARNINGS section of the package insert and a maximum aluminum content statement to the vial label as required by 21 CFR 201.323. PACKAGE INSERT (Plastic Vial) The following have been added as the third and fourth paragraphs to the WARNINGS section: 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-961/S-012 Page 2 VIAL LABEL (Plastic Vial) The following sentence was added after “See insert,” “Contains no more than 100 micrograms/Liter of aluminum.” We have completed the review of this supplemental application, as amended, and have concluded that adequate information has been presented to demonstrate that the drug product is safe and effective for use as recommended in the agreed upon labeling text. Accordingly, the supplemental application is approved effective on the date of this letter. The final printed labeling (FPL) must be identical to the submitted draft labeling (package insert submitted February 15, 2002 (marked up ID# 58-6220-R4 Rev. July 2001) and immediate container label submitted August 22, 2001 (ID# 58-2139-2/R4 – 7/01). Please submit the copies of final printed labeling (FPL) electronically according to the guidance for industry titled Providing Regulatory Submissions in Electronic Format - NDA (January 1999). Alternatively, you may submit 20 paper copies of the FPL as soon as it is available but no more than 30 days after it is printed. Please individually mount ten of the copies on heavy-weight paper or similar material. For administrative purposes, this submission should be designated "FPL for approved supplement NDA 18-961/S-012." Approval of this submission by FDA is not required before the labeling is used. If a letter communicating important information about this drug product (i.e., a "Dear Health Care Professional" letter) is issued to physicians and others responsible for patient care, we request that you submit a copy of the letter to this NDA and a copy to the following address: MEDWATCH, HF-2 FDA 5600 Fishers Lane Rockville, MD 20857 We remind you that you must comply with the requirements for an approved NDA set forth under 21 CFR 314.80 and 314.81. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-961/S-012 Page 3 If you have any questions, call Steve McCort, Regulatory Project Manager, at (301) 827-6415. Sincerely, {See appended electronic signature page} David G. Orloff, M.D. Director Division of Metabolic and Endocrine Drug Products Office of Drug Evaluation II Center for Drug Evaluation and Research This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 3 4 5 CHROMIUM 4 mcg/mL Chromic Chloride Injection, USP FOR I.V. USE ONLY AFTER DILUTION Plastic Vial only DESCRIPTION Chromium 4 mcg/mL (Chromic Chloride Injection, USP) is a sterile, nonpyrogenic solution intended for use as an additive to intravenous solutions for total parenteral nutrition (TPN). Each mL of solution contains 20.5 mcg chromic chloride, hexahydrate and 9 mg sodium chloride. The solution contains no bacteriostat, antimicrobial agent, or added buffer. The pH is 2.0 (1.5 to 2.5); product may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The osmolarity is 0.308 mOsm/mL (calc.). Chromic Chloride, USP is chemically designated chromic chloride, hexahydrate CrCl3 • 6H20, a crystalline compound soluble in water. Sodium Chloride, USP is chemically designated NaCl, a white, crystalline compound freely soluble in water. The semi-rigid vial is fabricated from a specially formulated polyolefin. It is a copolymer of ethylene and propylene. The safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers. The small amount of water vapor that can pass through the plastic container wall will not significantly alter the drug concentration. CLINICAL PHARMACOLOGY Trivalent chromium is part of glucose tolerance factor, an essential activator of insulin-mediated reactions. Chromium helps to maintain normal glucose metabolism and peripheral nerve function. Providing chromium during TPN helps prevent deficiency symptoms including impaired glucose tolerance, ataxia, peripheral neuropathy and a confusional state similar to mild/moderate hepatic encephalopathy. Serum chromium is bound to transferrin (siderophilin) in the beta globulin fraction. Typical blood levels for chromium range from 1 to 5 mcg/liter, but blood levels are not considered a meaningful index of tissue stores. Administration of chromium supplements to chromium- deficient patients can result in normalization of the glucose tolerance curve from the diabetic-like curve typical of chromium deficiency. This response is viewed as a more meaningful indicator of chromium nutriture than serum chromium levels. Excretion of chromium is via the kidneys, ranging from 3 to 50 mcg/day. Biliary excretion via the small intestine may be an ancillary route, but only small amounts of chromium are believed to be excreted in this manner. INDICATIONS AND USAGE Chromium 4 mcg/mL (Chromic Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Administration helps to maintain chromium serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms. CONTRAINDICATIONS None known. WARNINGS Direct intramuscular or intravenous injection of Chromium 4 mcg/mL (Chromic Chloride Injection, USP) is contraindicated, as the acidic pH of the solution may cause considerable tissue irritation. Severe kidney disease may make it necessary to reduce or omit chromium and zinc doses because these elements are primarily eliminated in the urine. 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. PRECAUTIONS General Do not use unless solution is clear and seal is intact. Chromium 4 mcg/mL (Chromic Chloride Injection, USP) should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed. In assessing the contribution of chromium supplements to maintenance of glucose homeostasis, consideration should be given to the possibility that the patient may be diabetic. 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. 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 ederly 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. Laboratory Tests Because chromium is present in the bloodstream in microgram quantities, routine measurement is impractical. If necessary, samples can be sent to a reference laboratory for assay. Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies to evaluate the carcinogenic potential of Chromium 4 mcg/mL (Chromic Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of 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 Chromium 4 mcg/mL (Chromic Chloride Injection, USP) is administered to a nursing woman. Pediatric Use See DOSAGE and ADMINISTRATION section. Safety and effectiveness in children have not been established. Pregnancy Category C. Animal reproduction studies have not been conducted with chromic chloride. It is also not known whether chromic chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Chromic chloride should be given to a pregnant woman only if clearly indicated. ADVERSE REACTIONS None known. DRUG ABUSE AND DEPENDENCE None known. OVERDOSAGE Trivalent chromium administered intravenously to TPN patients has been shown to be nontoxic when given at dosage levels of up to 250 mcg/day for two consecutive weeks. Reported toxic reactions to chromium include nausea, vomiting, ulcers of the gastrointestinal tract, renal and hepatic damage, convulsions and coma. The acute LD50 for intravenous trivalent chromium in rats was reported as 10 to 18 mg/kg. DOSAGE AND ADMINISTRATION Chromium 4 mcg/mL (Chromic Chloride Injection, USP) contains 4 mcg chromium/mL and is administered intravenously only after dilution. The additive should be administered in a volume of fluid not less than 100 mL. For the adult receiving TPN, the suggested additive dosage is 10 to 15 mcg chromium/day (2.5 to 3.75 mL/day). The metabolically stable adult with intestinal fluid loss may require 20 mcg chromium/day (5 mL/day), with frequent monitoring of blood levels as a guideline for subsequent administration. For pediatric patients, the suggested additive dosage is 0.14 to 0.20 mcg/kg/day (0.035 to 0.05 mL/kg/day). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS. HOW SUPPLIED Chromium 4 mcg/mL (Chromic Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4093). Store at controlled room temperature 15° to 30°C (59° to 86°F) (see USP). ©Abbott 2001 58-6220-R4-Rev. July, 2001 Printed in USA ABBOTT LABORATORIES, NORTH CHICAGO, IL 60064, USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 mL Vial NDC 0074-4093-01 ABBOTT LABORATORIES, N. CHICAGO, IL 60064, USA CHROMIUM 4 mcg/mL Chromic Chloride Inj., USP FOR I.V. USE ONLY AFTER DILUTION. Each mL contains chromic chloride, hexahydrate 20.5 mcg; sodium chloride 9 mg. 0.308 mOsmol/mL (calc). Usual dosage: See insert. Contains no more than 100 micrograms/Liter of aluminum. 58-2139-2/R4-7/01 a only This label may not be the latest approved by FDA. r current labeling information, please visit https://www.fda.gov/drugsatf --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Mary Parks 4/24/02 12:32:26 PM for Dr. Orloff This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:06.787163	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18961s12lbl.pdf', 'application_number': 18961, 'submission_type': 'SUPPL ', 'submission_number': 12}
11,379	Bipolar I Disorder fluoxetine once daily (initial mg of oral (2.5) dose) olanzapine and 20 mg of fluoxetine once daily (initial dose) Treatment Oral in combination with - Resistant olanzapine: 5 mg of oral Depression (2.6) olanzapine and 20 mg of fluoxetine once daily (initial dose) 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PROZAC safely and effectively. See full prescribing information for PROZAC. PROZAC (fluoxetine hydrochloride) Pulvules for oral use PROZAC (fluoxetine hydrochloride) delayed-release capsules for oral use Initial U.S. Approval: 1987 WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1). Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1). When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax. --------------------------- RECENT MAJOR CHANGES -------------------------- Boxed Warning: Warnings: Suicidal Thoughts and Behaviors MM/YYYY Indications and Usage: PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder (1.5) MM/YYYY Dosage and Administration: PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder (2.5) MM/YYYY Dosing in Specific Populations (2.7) MM/YYYY Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders (2.9) 01/2013 Use of PROZAC with Other MAOIs such as Linezolid or Methylene Blue (2.10) 01/2013 Contraindications: Monoamine Oxidase Inhibitors (MAOIs) (4.1) 01/2013 Other Contraindications (4.2) MM/YYYY Warnings and Precautions: Clinical Worsening and Suicide Risk (5.1) MM/YYYY Serotonin Syndrome (5.2) 01/2013 QT Prolongation (5.10) MM/YYYY ---------------------------- INDICATIONS AND USAGE --------------------------- PROZAC® is a selective serotonin reuptake inhibitor indicated for: • Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult and pediatric patients aged 8 to 18 years (1.1) • Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in adult and pediatric patients aged 7 to 17 years (1.2) • Acute and maintenance treatment of Bulimia Nervosa in adult patients (1.3) • Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients (1.4) PROZAC and olanzapine in combination for: • Acute treatment of Depressive Episodes Associated with Bipolar I Disorder (1.5) • Acute treatment of Treatment Resistant Depression in adults (1.6) ------------------------ DOSAGE AND ADMINISTRATION ----------------------- Indication Adult Pediatric MDD (2.1) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD (2.2) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa (2.3) 60 mg/day in am - Panic Disorder (2.4) 10 mg/day (initial dose) - Depressive Episodes Associated with Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of Oral in combination with olanzapine: 2.5 • A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.7) • Dosing with PROZAC Weekly capsules - initiate 7 days after the last daily dose of PROZAC 20 mg (2.1) PROZAC and olanzapine in combination: • Dosage adjustments should be made with the individual components according to efficacy and tolerability (2.5, 2.6) • Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder or treatment resistant depression (2.5, 2.6) • Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults (2.5, 2.6) • Safety of the coadministration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17 (2.5) DOSAGE FORMS AND STRENGTHS • Pulvules: 10 mg, 20 mg, 40 mg (3) • Weekly capsules: 90 mg (3) -------------------------------CONTRAINDICATIONS---------------------------- • Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with PROZAC or within 5 weeks of stopping treatment with PROZAC. Do not use PROZAC within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start PROZAC in a patient who is being treated with linezolid or intravenous methylene blue (4.1) • Pimozide: Do not use. Risk of QT prolongation and drug interaction (4.2, 5.10,7.7, 7.8) • Thioridazine: Do not use. Risk of QT interval prolongation and elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing PROZAC Do not use thioridazine within 5 weeks of discontinuing PROZAC (4.2, 5.10,7.7, 7.8). • When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax (4) ------------------------ WARNINGS AND PRECAUTIONS ----------------------- • Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1) • Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including PROZAC, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort). If such symptoms occur, discontinue PROZAC and initiate supportive treatment. If concomitant use of PROZAC with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. (5.2) • Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena (5.3) • Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4) • Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.5) • Altered Appetite and Weight: Significant weight loss has occurred (5.6) • Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.7) • Hyponatremia: Has been reported with PROZAC in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing if symptomatic hyponatremia occurs (5.8) • Anxiety and Insomnia: May occur (5.9) Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 • QT Prolongation: QT prolongation and ventricular arrhythmia including Torsade de Pointes have been reported with PROZAC use. Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation (4.2, 5.10, 7.7, 7.8, 10.1) • Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery (5.11) • Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks (5.12) • PROZAC and Olanzapine in Combination: When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax (5.14) ------------------------------- ADVERSE REACTIONS ------------------------------ Most common adverse reactions (≥5% and at least twice that for placebo) associated with: Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1) PROZAC and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for Symbyax (6) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800 FDA-1088 or www.fda.gov/medwatch ------------------------------- DRUG INTERACTIONS ------------------------------ • Monoamine Oxidase Inhibitors (MAOIs): (2.9, 2.10, 4.1, 5.2) • • Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7) • Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with PROZAC or when PROZAC has been recently discontinued (5.2, 7.7) • CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2) • Benzodiazepines: Diazepam – increased t½, alprazolam - further psychomotor performance decrement due to increased levels (7.7) • Antipsychotics: Potential for elevation of haloperidol and clozapine levels (7.7) • Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.7) • Serotonergic Drugs: (2.9, 2.10, 4.1, 5.2) • Drugs that Interfere with Hemostasis (e.g. NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding (7.4) • Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations (7.6, 7.7) • Olanzapine: When used in combination with PROZAC, also refer to the Drug Interactions section of the package insert for Symbyax (7.7) • Drugs that Prolong the QT Interval: Do not use Prozac with thioridazine or pimozide. Use with caution in combination with other drugs that prolong the QT interval (4.2, 5.10,7.7, 7.8) ------------------------ USE IN SPECIFIC POPULATIONS ----------------------- • Pregnancy: PROZAC should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus (8.1) • Nursing Mothers: Breast feeding is not recommended (8.3) • Pediatric Use: Safety and effectiveness of PROZAC in patients <8 years of age with Major Depressive Disorder and <7 years of age with OCD have not been established. Safety and effectiveness of PROZAC and olanzapine in combination in patients <10 years of age for depressive episodes associated with Bipolar I Disorder have not been established. (8.4) • Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis (8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved Medication Guide Revised: 00/0000 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SUICIDAL THOUGHTS AND BEHAVIORS 1 INDICATIONS AND USAGE 1.1 Major Depressive Disorder 1.2 Obsessive Compulsive Disorder 1.3 Bulimia Nervosa 1.4 Panic Disorder 1.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder 1.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression 2 DOSAGE AND ADMINISTRATION 2.1 Major Depressive Disorder 2.2 Obsessive Compulsive Disorder 2.3 Bulimia Nervosa 2.4 Panic Disorder 2.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder 2.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression 2.7 Dosing in Specific Populations 2.8 Discontinuation of Treatment 2.9 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders 2.10 Use of PROZAC with Other MAOIs such as Linezolid or Methylene Blue 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Monoamine Oxidase Inhibitors (MAOIs) 4.2 Other Contraindications 5 WARNINGS AND PRECAUTIONS 5.1 Clinical Worsening and Suicide Risk 5.2 Serotonin Syndrome 5.3 Allergic Reactions and Rash 5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 5.5 Seizures 5.6 Altered Appetite and Weight 5.7 Abnormal Bleeding 5.8 Hyponatremia 5.9 Anxiety and Insomnia 5.10 QT Prolongation 5.11 Use in Patients with Concomitant Illness 5.12 Potential for Cognitive and Motor Impairment 5.13 Long Elimination Half-Life 5.14 Discontinuation Adverse Reaction 5.15 PROZAC and Olanzapine in Combination 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Other Reactions 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Monoamine Oxidase Inhibitors (MAOI) 7.2 CNS Acting Drugs 7.3 Serotonergic Drugs 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) 7.5 Electroconvulsive Therapy (ECT) 7.6 Potential for Other Drugs to affect PROZAC 7.7 Potential for PROZAC to affect Other Drugs 7.8 Drugs that Prolong the QT Interval 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 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 9.3 Dependence 10 OVERDOSAGE 10.1 Human Experience 10.2 Animal Experience 10.3 Management of Overdose 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Specific Populations 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Major Depressive Disorder 14.2 Obsessive Compulsive Disorder 14.3 Bulimia Nervosa 14.4 Panic Disorder 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION 17.1 General Information 17.2 Clinical Worsening and Suicide Risk 17.3 Serotonin Syndrome 17.4 Allergic Reactions and Rash 17.5 Abnormal Bleeding 17.6 Hyponatremia 17.7 QT Prolongation 17.8 Potential for Cognitive and Motor Impairment 17.9 Use of Concomitant Medications 17.10 Discontinuation of Treatment 17.11 Use in Specific Populations Sections or subsections omitted from the full prescribing information are not listed Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 FULL PRESCRIBING INFORMATION WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1). PROZAC is not approved for use in children less than 7 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax. 1 INDICATIONS AND USAGE 1.1 Major Depressive Disorder PROZAC® is indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to 18 years [see Clinical Studies (14.1)]. The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods, should periodically be re-evaluated [see Dosage and Administration (2.1)]. 1.2 Obsessive Compulsive Disorder PROZAC is indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2)]. The effectiveness of PROZAC in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use PROZAC for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.2)]. 1.3 Bulimia Nervosa PROZAC is indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)]. The physician who elects to use PROZAC for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)]. 1.4 Panic Disorder PROZAC is indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [see Clinical Studies (14.4)]. The effectiveness of PROZAC in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use PROZAC for extended periods, should periodically re evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.4)]. 1.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax® . PROZAC and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. 1.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. PROZAC and olanzapine in combination is indicated for the acute treatment of treatment resistant depression (Major Depressive Disorder in adult patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode). PROZAC monotherapy is not indicated for the treatment of treatment resistant depression. 2 DOSAGE AND ADMINISTRATION Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 2.1 Major Depressive Disorder Initial Treatment Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies (14.1)]. Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Daily Dosing — Systematic evaluation of PROZAC in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day [see Clinical Studies (14.1)]. Weekly Dosing — Systematic evaluation of PROZAC® Weekly™ in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment with PROZAC 20 mg once daily. However, therapeutic equivalence of PROZAC Weekly given on a once-weekly basis with PROZAC 20 mg given daily for delaying time to relapse has not been established [see Clinical Studies (14.1)]. Weekly dosing with PROZAC Weekly capsules is recommended to be initiated 7 days after the last daily dose of PROZAC 20 mg [see Clinical Pharmacology (12.3)]. If satisfactory response is not maintained with PROZAC Weekly, consider reestablishing a daily dosing regimen [see Clinical Studies (14.1)]. Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Drug Interactions (7.7)]. 2.2 Obsessive Compulsive Disorder Initial Treatment Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)]. In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue PROZAC, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of PROZAC after 13 weeks has not been documented in controlled trials, adult patients Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. 2.3 Bulimia Nervosa Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo [see Clinical Studies (14.3)]. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. Maintenance/Continuation Treatment — Systematic evaluation of continuing PROZAC 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking PROZAC 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment [see Clinical Studies (14.3)]. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. 2.4 Panic Disorder Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.4)]. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue PROZAC, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. 2.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adult — Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. Children and adolescents (10 -17 years of age) — Olanzapine and fluoxetine combination should be administered once daily in the evening, generally beginning with 2.5 mg of olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg of olanzapine with 50 mg of fluoxetine has not been evaluated in pediatric clinical studies. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. Table 1: Approximate Dose Correspondence Between Symbyax1 and the Combination of PROZAC and Olanzapine For Use in Combination Symbyax (mg/day) Olanzapine (mg/day) PROZAC (mg/day) 3 mg olanzapine/25 mg fluoxetine 2.5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 1 Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of PROZAC and olanzapine. While there is no body of evidence to answer the question of how long a patient treated with PROZAC and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. 2.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 20 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. While there is no body of evidence to answer the question of how long a patient treated with PROZAC and olanzapine in combination should remain on it, it is generally accepted that treatment resistant depression (Major Depressive Disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. PROZAC monotherapy is not indicated for the treatment of treatment resistant depression (Major Depressive Disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode). 2.7 Dosing in Specific Populations Treatment of Pregnant Women — When treating pregnant women with PROZAC, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations (8.1)]. Geriatric — A lower or less frequent dosage should be considered for the elderly [see Use in Specific Populations (8.5)] Hepatic Impairment — As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment [see Clinical Pharmacology (12.4) and Use in Specific Populations (8.6)]. Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology (12.4) and Warnings and Precautions (5.10)]. PROZAC and Olanzapine in Combination — The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modifications may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. PROZAC and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 10 years of age [see Warnings and Precautions (5.14) and Drug Interactions (7.7)]. 2.8 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.13)]. 2.9 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 PROZAC. Conversely, at least 5 weeks should be allowed after stopping PROZAC before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)]. 2.10 Use of PROZAC with Other MAOIs such as Linezolid or Methylene Blue Do not start PROZAC in a patient who is being treated with linezolid or intravenous methylene blue because there is an 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 (4.1)]. In some cases, a patient already receiving PROZAC 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, PROZAC should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 PROZAC may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)]. 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 PROZAC is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)]. 3 DOSAGE FORMS AND STRENGTHS • 10 mg Pulvule is an opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body • 20 mg Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body • 40 mg Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body • 90 mg Prozac Weekly™ Capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body 4 CONTRAINDICATIONS When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with PROZAC or within 5 weeks of stopping treatment with PROZAC is contraindicated because of an increased risk of serotonin syndrome. The use of PROZAC within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.9) and Warnings and Precautions (5.2)]. Starting PROZAC 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 Dosage and Administration (2.10) and Warnings and Precautions (5.2)]. 4.2 Other Contraindications The use of PROZAC is contraindicated with the following: • Pimozide [see Warnings and Precautions (5.10) and Drug Interactions (7.7, 7.8)] • Thioridazine [see Warnings and Precautions (5.10) and Drug Interactions (7.7, 7.8)] Pimozide and thioridazine prolong the QT interval. PROZAC can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. PROZAC can also prolong the QT interval. 5 WARNINGS AND PRECAUTIONS When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. 5.1 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 versus 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 2. Table 2: Suicidality per 1000 Patients Treated Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 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. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.13)]. 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 PROZAC should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. It should be noted that PROZAC is approved in the pediatric population for Major Depressive Disorder and Obsessive Compulsive Disorder; and PROZAC in combination with olanzapine for the acute treatment of depressive episodes associated with Bipolar I Disorder. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including PROZAC, 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 PROZAC with MAOIs intended to treat psychiatric disorders is contraindicated. PROZAC 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 1mg/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 PROZAC. PROZAC should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) and Dosage and Administration (2.9, 2.10)]. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 If concomitant use of PROZAC with other serotonergic drugs, i.e., 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 PROZAC and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.3 Allergic Reactions and Rash In US fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely. In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of PROZAC, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions. Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom. Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, PROZAC should be discontinued. 5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 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 for clinical worsening and suicide risk 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 PROZAC and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions section of the package insert for Symbyax]. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with PROZAC and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see Use in Specific Populations (8.4)]. In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with PROZAC and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In US PROZAC clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)]. 5.5 Seizures In US placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with PROZAC and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In US PROZAC clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. PROZAC should be introduced with care in patients with a history of seizures. 5.6 Altered Appetite and Weight Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with PROZAC. In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with PROZAC and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 treated with PROZAC and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with PROZAC because of anorexia or weight loss [see Use in Specific Populations (8.4)]. In US placebo-controlled clinical trials for OCD, 17% of patients treated with PROZAC and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with PROZAC because of anorexia [see Use in Specific Populations (8.4)]. In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with PROZAC 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with PROZAC 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy. 5.7 Abnormal Bleeding SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.4)]. 5.8 Hyponatremia Hyponatremia has been reported during treatment with SNRIs and SSRIs, including PROZAC. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when PROZAC was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of PROZAC should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.9 Anxiety and Insomnia In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with PROZAC and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with PROZAC and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with PROZAC and in 7% of patients treated with placebo. In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with PROZAC 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with PROZAC 60 mg and in 9% and 5% of patients treated with placebo. Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5]. 5.10 QT Prolongation Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsade de Pointes have been reported in patients treated with PROZAC. PROZAC should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). PROZAC is primarily metabolized by CYP2D6 [see Contraindications (4.2), Drug Interactions (7.7, 7.8), Overdose (10.1), and Clinical Pharmacology (12.3)]. Pimozide and thioridazine are contraindicated for use with PROZAC. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g.,erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions (7.7, 7.8) and Clinical Pharmacology (12.3)]. Consider ECG assessment and periodic ECG monitoring if initiating treatment with PROZAC in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing PROZAC and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 5.11 Use in Patients with Concomitant Illness Clinical experience with PROZAC in patients with concomitant systemic illness is limited. Caution is advisable in using PROZAC in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received PROZAC in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. Glycemic Control — In patients with diabetes, PROZAC may alter glycemic control. Hypoglycemia has occurred during therapy with PROZAC, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with PROZAC is instituted or discontinued. Acute Narrow-Angle Glaucoma — Mydriasis has been reported in association with PROZAC; therefore, caution should be used when prescribing PROZAC in patients with raised intraocular pressure or those at risk of acute narrow- angle glaucoma. 5.12 Potential for Cognitive and Motor Impairment As with any CNS-active drug, PROZAC has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. 5.13 Long Elimination Half-Life Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see Clinical Pharmacology (12.3)]. 5.14 Discontinuation Adverse Reactions During marketing of PROZAC, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with PROZAC. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. 5.15 PROZAC and Olanzapine in Combination When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. 6 ADVERSE REACTIONS When using PROZAC and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of PROZAC have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered PROZAC in panic clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that reactions reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use of PROZAC (incidence of at least 5% for PROZAC and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, OCD, and bulimia in US controlled clinical trials and Panic Disorder in US plus non-US controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with PROZAC and with incidence greater than placebo who participated in US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3. Table 3: Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1,2 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Reaction PROZA C (N=172 8) Placebo (N=975) PROZAC (N=266) Placeb o (N=89) PROZAC (N=450) Placebo (N=267) PROZAC (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn - - 7 - 11 - 1 - Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence3 2 - - - 7 - 1 - Abnormal ejaculation3 - - 7 - 7 - 2 1 Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 1 Incidence less than 1%. 2 Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. 3 Denominator used was for males only (N=690 PROZAC Major Depressive Disorder; N=410 placebo Major Depressive Disorder; N=116 PROZAC OCD; N=43 placebo OCD; N=14 PROZAC bulimia; N=1 placebo bulimia; N=162 PROZAC panic; N=121 placebo panic). Table 4: Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1,2 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Reaction PROZAC (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 1 Incidence less than 1%. 2 Includes US data for Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 5 lists the adverse reactions associated with discontinuation of PROZAC treatment (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Table 5: Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) - Anxiety (2%) - Anxiety (2%) - - - Insomnia (2%) - - Nervousness (1%) - - Nervousness (1%) - - Rash (1%) - - 1 Includes US Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials. Other adverse reactions in pediatric patients (children and adolescents) — Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected. Reactions observed in PROZAC Weekly clinical trials — Treatment-emergent adverse reactions in clinical trials with PROZAC Weekly were similar to the adverse reactions reported by patients in clinical trials with PROZAC daily. In a placebo-controlled clinical trial, more patients taking PROZAC Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking PROZAC 20 mg daily (10% versus 5%, respectively). Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, 1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. 6.2 Other Reactions Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction. Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia, hypotension1 . Digestive System — Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage. Hemic and Lymphatic System — Infrequent: ecchymosis; Rare: petechia, purpura. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder1, bruxism1 , buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions. Respiratory System — Rare: larynx edema. Skin and Appendages — Infrequent: alopecia; Rare: purpuric rash. Special Senses — Frequent: taste perversion; Infrequent: mydriasis. Urogenital System — Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding2 . 1 MedDRA dictionary term from integrated database of placebo controlled trials of 15870 patients, of which 9673 patients received fluoxetine. 2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of PROZAC. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with PROZAC that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, pancreatitis1 , pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including torsades de pointes–type arrhythmias), vaginal bleeding, and violent behaviors1 . 1 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. 7 DRUG INTERACTIONS As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. 7.1 Monoamine Oxidase Inhibitors (MAOI) [see Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)]. 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of PROZAC and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)]. 7.3 Serotonergic Drugs [see Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)]. 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7)]. 7.5 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. 7.6 Potential for Other Drugs to affect PROZAC Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs [see Clinical Pharmacology (12.3)]. 7.7 Potential for PROZAC to affect Other Drugs Pimozide — Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and PROZAC [see Contraindications (4.2), Warnings and Precautions (5.10), and Drug Interactions (7.8)]. Thioridazine — Thioridazine should not be administered with PROZAC or within a minimum of 5 weeks after PROZAC has been discontinued, because of the risk of QT Prolongation [see Contraindications (4.2), Warnings and Precautions (5.10), and Drug Interactions (7.8)]. In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine. Thioridazine administration produces a dose-related prolongation of the QTinterval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Drugs Metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4.2)]. Tricyclic Antidepressants (TCAs) — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly [see Warnings and Precautions (5.2)]. Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect [see Clinical Pharmacology (12.3)]. Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Olanzapine— Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using PROZAC and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax. 7.8 Drugs that Prolong the QT Interval Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Do not use PROZAC in combination with thioridazine or pimozide. Use PROZAC with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). PROZAC is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of PROZAC. Concomitant use of other highly protein-bound drugs can increase the concentration of PROZAC [see Contraindications (4.2), Warnings and Precautions (5.10), Drug Interactions (7.7), and Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS When using PROZAC and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. 8.1 Pregnancy Pregnancy Category C — PROZAC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. Treatment of Pregnant Women during the First Trimester — There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. Nonteratogenic Effects — Neonates exposed to PROZAC and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 - 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including PROZAC) in pregnancy and PPHN. Other studies do not show a significant statistical association. Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with PROZAC, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis [see Dosage and Administration (2.7)]. Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). 8.2 Labor and Delivery The effect of PROZAC on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Because PROZAC is excreted in human milk, nursing while on PROZAC is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on PROZAC Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. 8.4 Pediatric Use Use of PROZAC in children - The efficacy of PROZAC for the treatment of Major Depressive Disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to 18 [see Clinical Studies (14.1)]. The efficacy of PROZAC for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 [see Clinical Studies (14.2)]. The safety and effectiveness in pediatric patients <8 years of age in Major Depressive Disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with Major Depressive Disorder or OCD [see Clinical Pharmacology (12.3)]. The acute adverse reaction profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19-week Major Depressive Disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see Adverse Reactions (6.1)]. Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. [see Warnings and Precautions (5.6)]. PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Anyone considering the use of PROZAC in a child or adolescent must balance the potential risks with the clinical need. Animal Data Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5-10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1-2 times the average AUC in pediatric patients at the MRHD of 20mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5 10 times the average AUC in pediatric patients at the MRHD of 20mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1-0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30mg/kg/day doses in this study are approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, are approximately 0.3-0.8, 1-8, and 3-20 times, respectively, the pediatric exposure at the MRHD. A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. Use of PROZAC in combination with olanzapine in children and adolescents: Safety and efficacy of PROZAC and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with Bipolar I Disorder. Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 10 years of age have not been established. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 8.5 Geriatric Use US fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.4)]. No overall differences in safety or 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. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.8)]. Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using PROZAC in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.7) and Clinical Pharmacology (12.4)]. 9 DRUG ABUSE AND DEPENDENCE 9.3 Dependence PROZAC has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with PROZAC did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of PROZAC (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). 10 OVERDOSAGE 10.1 Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as nodal rhythm, QT interval prolongation and ventriculararrhythmias, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope. 10.2 Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see Overdosage (10.3)]. 10.3 Management of Overdose For current information on the management of PROZAC overdose, contact a certified poison control center (1-800 222-1222 or www.poison.org). Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multi-drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use general supportive and symptomatic measures. Induction of emesis is not recommended. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Drug Interactions (7.7)]. For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert. 11 DESCRIPTION PROZAC® (fluoxetine capsules, USP) is a selective serotonin reuptake inhibitor for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: s truc tural formula Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol), 20 mg (64.7 µmol), or 40 mg (129.3 µmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10 and 20 mg Pulvules also contain FD&C Blue No. 1, and the 40 mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. PROZAC Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 µmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Although the exact mechanism of PROZAC is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. 12.2 Pharmacodynamics Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. 12.3 Pharmacokinetics Systemic Bioavailability — In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The Pulvule and PROZAC Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. PROZAC Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. Protein Binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important. Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions (7.7)]. Accumulation and Slow Elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used [see Warnings and Precautions (5.12)]. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of PROZAC. Weekly Dosing — Administration of PROZAC Weekly once weekly results in increased fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of clinical response. Peak concentrations from once-weekly doses of PROZAC Weekly capsules of fluoxetine are in the range of the average concentration for 20 mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20 mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly dosing are in relative proportion to the total dose administered. Average steady-state fluoxetine concentrations are approximately 50% lower following the once-weekly regimen compared with the once-daily regimen. Cmax for fluoxetine following the 90 mg dose was approximately 1.7-fold higher than the Cmax value for the established 20 mg once-daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90 mg once-weekly dose and the last 20 mg once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better to separate the first 90 mg weekly dose and the last 20 mg once-daily dose by 1 week [see Dosage and Administration (2.1)]. 12.4 Specific Populations Liver Disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used [see Dosage and Administration (2.7), Use in Specific Populations (8.6)]. Renal Disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. Geriatric Pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients. Pediatric Pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with Major Depressive Disorder or Obsessive Compulsive Disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with Major Depressive Disorder. Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity. Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of Fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)]. 13.2 Animal Toxicology and/or Pharmacology Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. 14 CLINICAL STUDIES When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. 14.1 Major Depressive Disorder Daily Dosing Adult — The efficacy of PROZAC was studied in 5- and 6-week placebo-controlled trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of Major Depressive Disorder. PROZAC was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). PROZAC was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. Two 6-week controlled studies (N=671, randomized) comparing PROZAC 20 mg and placebo have shown PROZAC 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with Major Depressive Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 Disorder. In these studies, PROZAC produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. PROZAC was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between PROZAC (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on PROZAC 20 mg/day. These patients (N=298) were randomized to continuation on double-blind PROZAC 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking PROZAC compared with those on placebo. Pediatric (children and adolescents) — The efficacy of PROZAC 20 mg/day in children and adolescents (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) was studied in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of Major Depressive Disorder. In both studies independently, PROZAC produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Weekly dosing for Maintenance/Continuation Treatment A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for Major Depressive Disorder who had responded (defined as having a modified HAMD-17 score of ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for Major Depressive Disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with PROZAC 20 mg once daily. These patients were randomized to double-blind, once-weekly continuation treatment with PROZAC Weekly, PROZAC 20 mg once daily, or placebo. PROZAC Weekly once weekly and PROZAC 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of depressive symptoms) compared with placebo for a period of 25 weeks. However, the equivalence of these 2 treatments during continuation therapy has not been established. 14.2 Obsessive Compulsive Disorder Adult — The effectiveness of PROZAC for the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed PROZAC doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving PROZAC experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving PROZAC experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: Table 6 Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies PROZAC Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD (DSM-IV), patients received PROZAC 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. PROZAC produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. 14.3 Bulimia Nervosa Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________ 25 The effectiveness of PROZAC for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of PROZAC or placebo in the morning. Patients in the 16-week study received a fixed PROZAC dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, PROZAC 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The PROZAC-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between PROZAC 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with PROZAC 60 mg/day, were randomized to continuation of PROZAC 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued PROZAC 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. 14.4 Panic Disorder The effectiveness of PROZAC in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia. Study 1 (N=180 randomized) was a 12-week flexible-dose study. PROZAC was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of PROZAC-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N=214 randomized) was a 12-week flexible-dose study. PROZAC was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of PROZAC-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied The following products are manufactured by Eli Lilly and Company for Dista Products Company: Pulvule are available in 10mg, 20mg and 40mg capsule strengths and packages as follows: Pulvule Strength 10 mg1 20 mg1 40 mg1 Pulvule No.2 PU3104 PU3105 PU3107 Cap Color Opaque green Opaque green Opaque green Body Color Opaque green Opaque yellow Opaque orange Identification DISTA 3104 Prozac 10 mg DISTA 3105 Prozac 20 mg DISTA 3107 Prozac 40 mg NDC Codes: Bottles of 30 0777-3105-30 0777-3107-30 Bottles 100 0777-3104-02 0777-3105-02 Bottles of 2000 0777-3105-07 The following product is manufactured and distributed by Eli Lilly and Company: PROZAC® Weekly™ Capsules are available in: The 90 mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) – Blister package of 4 1 Fluoxetine base equivalent. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 2 Protect from light. 16.2 Storage and Handling Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). 17 PATIENT COUNSELING INFORMATION See the FDA-approved Medication Guide. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking PROZAC as monotherapy or in combination with olanzapine. When using PROZAC and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax. 17.1 General Information Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with PROZAC and to reread it each time the prescription is renewed. Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with PROZAC and should counsel them in its appropriate use. Healthcare providers 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. Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking PROZAC. When using PROZAC and olanzapine in combination, also refer to the Medication Guide for Symbyax. 17.2 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 [see Box Warning and Warnings and Precautions (5.1)]. 17.3 Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of PROZAC and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort [see Contraindications (4.1), Warnings and Precautions (5.2), and Drug Interactions (7.3)]. Patients should be advised of the signs and symptoms associated with serotonin syndrome that 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 cautioned to seek medical care immediately if they experience these symptoms. 17.4 Allergic Reactions and Rash Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions (5.3)]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms. 17.5 Abnormal Bleeding Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see Warnings and Precautions (5.7) and Drug Interactions (7.4)]. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking PROZAC. 17.6 Hyponatremia Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including PROZAC. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions (5.8)]. 17.7 QT Prolongation Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsade de Pointes have been reported in patients treated with PROZAC. Signs and symptoms of ventricular arrhythmia include fast, slow, or Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia [see Warnings and Precautions (5.10)]. 17.8 Potential for Cognitive and Motor Impairment PROZAC may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions (5.11)]. 17.9 Use of Concomitant Medications Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax, Sarafem, or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on PROZAC. 17.10 Discontinuation of Treatment Patients should be advised to take PROZAC exactly as prescribed, and to continue taking PROZAC as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking PROZAC without consulting their physician [see Warnings and Precautions (5.13)]. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with PROZAC. 17.11 Use in Specific Populations Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. Nursing Mothers — Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy. Because PROZAC is excreted in human milk, nursing while taking PROZAC is not recommended [see Use in Specific Populations (8.3)]. Pediatric Use of PROZAC — PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine. [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)]. Pediatric Use of PROZAC and olanzapine in combination - Safety and efficacy of PROZAC and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions (5.14) and Use in Specific Populations (8.4)]. Literature revised Month dd, yyyy Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 1987, yyyy, Eli Lilly and Company. All rights reserved. B5.0NL7433DPP Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 B2.0NL7104AMP Medication Guide PROZAC® (PRO-zac) (fluoxetine hydrochloride) Pulvule® and Weekly™ Capsule Read the Medication Guide that comes with PROZAC before you start 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 healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about PROZAC? PROZAC and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: • PROZAC and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. • Watch for these changes and call your healthcare provider right away if you notice: • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. • Pay particular attention to such changes when PROZAC is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: • attempts to commit suicide • acting on dangerous impulses • acting aggressive or violent • thoughts about suicide or dying • new or worse depression • new or worse anxiety or panic attacks • feeling agitated, restless, angry or irritable • trouble sleeping Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 • an increase in activity or talking more than what is normal for you • other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. PROZAC may be associated with these serious side effects: 2. Serotonin Syndrome. This condition can be life-threatening and may include: • agitation, hallucinations, coma or other changes in mental status • coordination problems or muscle twitching (overactive reflexes) • racing heartbeat, high or low blood pressure • sweating or fever • nausea, vomiting, or diarrhea • muscle rigidity • dizziness • flushing • tremor • seizures 3. Severe allergic reactions: • trouble breathing • swelling of the face, tongue, eyes or mouth • rash, itchy welts (hives) or blisters, alone or with fever or joint pain 4. Abnormal bleeding: PROZAC and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 5. Seizures or convulsions 6. Manic episodes: • greatly increased energy • severe trouble sleeping • racing thoughts • reckless behavior • unusually grand ideas • excessive happiness or irritability • talking more or faster than usual 7. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include: • headache • weakness or feeling unsteady • confusion, problems concentrating or thinking or memory problems 9. Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsade de Pointes). This condition can be life threatening. The symptoms may include: • fast, slow, or irregular heartbeat • shortness of breath • dizziness or fainting Do not stop PROZAC without first talking to your healthcare provider. Stopping PROZAC too quickly may cause serious symptoms including: • anxiety, irritability, high or low mood, feeling restless or changes in sleep habits • headache, sweating, nausea, dizziness • electric shock-like sensations, shaking, confusion What is PROZAC? PROZAC is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. PROZAC is used to treat: • Major Depressive Disorder (MDD) • Obsessive Compulsive Disorder (OCD) • Bulimia Nervosa • Panic Disorder* • Depressive episodes associated with Bipolar I Disorder, taken with olanzapine (Zyprexa) • Treatment Resistant Depression (depression that has not gotten better with at least 2 other treatments), taken with olanzapine (Zyprexa)* *Not approved for use in children Talk to your healthcare provider if you do not think that your condition is getting better with PROZAC treatment. Who should not take PROZAC? Do not take PROZAC if you: Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 • are allergic to fluoxetine hydrochloride or any of the ingredients in PROZAC. See the end of this Medication Guide for a complete list of ingredients in PROZAC. • 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 5 weeks of stopping PROZAC unless directed to do so by your physician. • Do not start PROZAC if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take PROZAC close in time to an MAOI may have serious or even life- threatening side effects. Get medical help right away if you have any of these symptoms: • high fever • uncontrolled muscle spasms • stiff muscles • rapid changes in heart rate or blood pressure • confusion • loss of consciousness (pass out) • take Mellaril® (thioridazine). Do not take Mellaril® within 5 weeks of stopping PROZAC because this can cause serious heart rhythm problems or sudden death. • take the antipsychotic medicine pimozide (Orap®) because this can cause serious heart problems. What should I tell my healthcare provider before taking PROZAC? Ask if you are not sure. Before starting PROZAC, tell your healthcare provider if you: • Are taking certain drugs or treatments such as: • Triptans used to treat migraine headache • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs, MAOIs or antipsychotics • Tramadol and fentanyl • Over-the-counter supplements such as tryptophan or St. John’s Wort • Electroconvulsive therapy (ECT) • have liver problems • have kidney problems • have heart problems • have or had seizures or convulsions • have bipolar disorder or mania Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 • have low sodium levels in your blood • have a history of a stroke • have high blood pressure • have or had bleeding problems • are pregnant or plan to become pregnant. It is not known if PROZAC will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy. • are breast-feeding or plan to breast-feed. Some PROZAC may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking PROZAC. Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. PROZAC and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take PROZAC with your other medicines. Do not start or stop any medicine while taking PROZAC without talking to your healthcare provider first. If you take PROZAC, you should not take any other medicines that contain fluoxetine hydrochloride including: • Symbyax • Sarafem • Prozac Weekly How should I take PROZAC? • Take PROZAC exactly as prescribed. Your healthcare provider may need to change the dose of PROZAC until it is the right dose for you. • PROZAC may be taken with or without food. • If you miss a dose of PROZAC, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of PROZAC at the same time. • If you take too much PROZAC, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking PROZAC? PROZAC can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how PROZAC affects you. Do not drink alcohol while using PROZAC. What are the possible side effects of PROZAC? PROZAC may cause serious side effects, including: Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 • See “What is the most important information I should know about PROZAC?” • Problems with blood sugar control. People who have diabetes and take PROZAC may have problems with low blood sugar while taking PROZAC. High blood sugar can happen when PROZAC is stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking PROZAC. • Feeling anxious or trouble sleeping Common possible side effects in people who take PROZAC include: • unusual dreams • sexual problems • loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth • flu symptoms • feeling tired or fatigued • change in sleep habits • yawning • sinus infection or sore throat • tremor or shaking • sweating • feeling anxious or nervous • hot flashes • rash Other side effects in children and adolescents include: • increased thirst • abnormal increase in muscle movement or agitation • nose bleed • urinating more often • heavy menstrual periods • possible slowed growth rate and weight change. Your child’s height and weight should be monitored during treatment with PROZAC. 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 PROZAC. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 How should I store PROZAC? • Store PROZAC at room temperature between 59°F and 86°F (15°C to 30°C). • Keep PROZAC away from light. • Keep PROZAC bottle closed tightly. Keep PROZAC and all medicines out of the reach of children. General information about PROZAC Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PROZAC for a condition for which it was not prescribed. Do not give PROZAC to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about PROZAC. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about PROZAC that is written for healthcare professionals. For more information about PROZAC call 1-800-Lilly-Rx (1-800-545-5979). What are the ingredients in PROZAC? Active ingredient: fluoxetine hydrochloride Inactive ingredients: • PROZAC pulvules: starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10 and 20 mg Pulvules also contain FD&C Blue No. 1, and the 40 mg Pulvules also contains FD&C Blue No. 1 and FD&C Yellow No. 6. • PROZAC Weekly™ capsules: D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium oxide, triethyl citrate, and other inactive ingredients. This Medication Guide has been approved by the U.S. Food and Drug Administration. Medication Guide revised Month dd, yyyy Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 2009, yyyy, Eli Lilly and Company. All rights reserved. B3.0NL7104AMP Reference ID: 3347923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:06.982367	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018936s100s101,021235s021lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 100}
11,385	1 1 EC-NAPROSYN® (naproxen delayed-release tablets) 2 NAPROSYN® (naproxen tablets) 3 ANAPROX®/ANAPROX®DS (naproxen sodium tablets) 4 NAPROSYN®(naproxen suspension) 5 Rx only 6 7 8 9 DESCRIPTION 10 Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory 11 drugs. 12 The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2- 13 naphthaleneacetic acid and (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, sodium 14 salt, respectively. Naproxen and naproxen sodium have the following structures, 15 respectively: 16 17 Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. 18 Naproxen sodium has a molecular weight of 252.23 and a molecular formula of 19 C14H13NaO3. 20 Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, 21 practically insoluble in water at low pH and freely soluble in water at high pH. The 22 octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium 23 is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. 24 NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of 25 naproxen, peach tablets containing 375 mg of naproxen and yellow tablets containing 500 26 mg of naproxen for oral administration. The inactive ingredients are croscarmellose 27 sodium, iron oxides, povidone and magnesium stearate. 28 EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-coated white 29 tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration. 30 The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate. 31 The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, 32 sodium hydroxide and purified water. The dispersion may also contain simethicone 33 emulsion. The dissolution of this enteric-coated naproxen tablet is pH dependent with 34 rapid dissolution above pH 6. There is no dissolution below pH 4. 35 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 2 ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg of 36 naproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue 37 tablets containing 550 mg of naproxen sodium for oral administration. The inactive 38 ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The 39 coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl 40 methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1- 41 4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain 42 hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or 43 Opadry YS-1-4216. 44 NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral 45 suspension containing 125 mg/5 mL of naproxen in a vehicle containing sucrose, 46 magnesium aluminum silicate, sorbitol solution and sodium chloride (30 mg/5 mL, 1.5 47 mEq), methylparaben, fumaric acid, FD&C Yellow No. 6, imitation pineapple flavor, 48 imitation orange flavor and purified water. The pH of the suspension ranges from 2.2 to 49 3.7. 50 CLINICAL PHARMACOLOGY 51 Pharmacodynamics: Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with 52 analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a 53 more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism 54 of action of the naproxen anion, like that of other NSAIDs, is not completely understood 55 but may be related to prostaglandin synthetase inhibition. 56 Pharmacokinetics: Naproxen itself is rapidly and completely absorbed from the 57 gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms 58 of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak 59 concentration (Cmax); however, the products do differ in their pattern of absorption. These 60 differences between naproxen products are related to both the chemical form of naproxen 61 used and its formulation. Even with the observed differences in pattern of absorption, the 62 elimination half-life of naproxen is unchanged across products ranging from 12 to 17 63 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of 64 naproxen accumulation is consistent with this half-life. This suggests that the differences 65 in pattern of release play only a negligible role in the attainment of steady-state plasma 66 levels. 67 Absorption: 68 Immediate Release: After administration of NAPROSYN tablets, peak plasma levels are 69 attained in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels are 70 attained in 1 to 2 hours. The difference in rates between the two products is due to the 71 increased aqueous solubility of the sodium salt of naproxen used in ANAPROX. Peak 72 plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours. 73 Delayed Release: EC-NAPROSYN is designed with a pH-sensitive coating to provide a 74 barrier to disintegration in the acidic environment of the stomach and to lose integrity in 75 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 3 the more neutral environment of the small intestine. The enteric polymer coating selected 76 for EC-NAPROSYN dissolves above pH 6. When EC-NAPROSYN was given to fasted 77 subjects, peak plasma levels were attained about 4 to 6 hours following the first dose 78 (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC-NAPROSYN 79 tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine 80 rather than the stomach, so the absorption of the drug is delayed until the stomach is 81 emptied. 82 When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a 83 crossover study following 1 week of dosing, differences in time to peak plasma levels 84 (Tmax) were observed, but there were no differences in total absorption as measured by 85 Cmax and AUC: 86 EC-NAPROSYN* 500 mg bid NAPROSYN* 500 mg bid Cmax (µg/mL) 94.9 (18%) 97.4 (13%) Tmax (hours) 4 (39%) 1.9 (61%) AUC0–12 hr (µg·hr/mL) 845 (20%) 767 (15%) Mean value (coefficient of variation) 87 Antacid Effects: When EC-NAPROSYN was given as a single dose with antacid (54 mEq 88 buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to 89 peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although 90 not significantly. 91 Food Effects: When EC-NAPROSYN was given as a single dose with food, peak plasma 92 levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence 93 time in the small intestine until disintegration was independent of food intake. The 94 presence of food prolonged the time the tablets remained in the stomach, time to first 95 detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did 96 not affect peak naproxen levels (Cmax). 97 Distribution: 98 Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is 99 greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is 100 less than proportional increase in plasma levels due to an increase in clearance caused by 101 saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 102 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen). The naproxen anion 103 has been found in the milk of lactating women at a concentrations equivalent to 104 approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS: 105 Nursing Mothers). 106 Metabolism: 107 Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and 108 metabolites do not induce metabolizing enzymes. 109 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 4 Excretion: 110 The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from 111 any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl 112 naproxen (less than 1%) or their conjugates (66% to 92%). The plasma half-life of the 113 naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of 114 both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of 115 excretion have been found to coincide closely with the rate of naproxen disappearance 116 from the plasma. In patients with renal failure metabolites may accumulate (see 117 PRECAUTIONS: Renal Effects). 118 Special Populations: 119 Pediatric Patients: In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen 120 levels following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND 121 ADMINISTRATION) were found to be similar to those found in normal adults following 122 a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. 123 Pharmacokinetic studies of naproxen were not performed in pediatric patients younger 124 than 5 years of age. Pharmacokinetic parameters appear to be similar following 125 administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN 126 has not been studied in subjects under the age of 18. 127 Geriatric Patients: Studies indicate that although total plasma concentration of naproxen 128 is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, 129 although the unbound fraction is less than 1% of the total naproxen concentration. 130 Unbound trough naproxen concentrations in elderly subjects have been reported to range 131 from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% 132 in younger subjects. The clinical significance of this finding is unclear, although it is 133 possible that the increase in free naproxen concentration could be associated with an 134 increase in the rate of adverse events per a given dosage in some elderly patients. 135 Race: Pharmacokinetic differences due to race have not been studied. 136 Hepatic Insufficiency: Naproxen pharmacokinetics has not been determined in subjects 137 with hepatic insufficiency. 138 Renal Insufficiency: Naproxen pharmacokinetics has not been determined in subjects 139 with renal insufficiency. Given that naproxen, its metabolites and conjugates are 140 primarily excreted by the kidney, the potential exists for naproxen metabolites to 141 accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased 142 in patients with severe renal impairment. Naproxen-containing products are not 143 recommended for use in patients with moderate to severe and severe renal impairment 144 (creatinine < 30 ml/min) (see PRECAUTIONS: Renal Effects). 145 CLINICAL STUDIES 146 General Information: Naproxen has been studied in patients with rheumatoid arthritis, 147 osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute 148 gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a 149 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 5 reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in 150 disease activity as assessed by both the investigator and patient, and by increased 151 mobility as demonstrated by a reduction in walking time. Generally, response to 152 naproxen has not been found to be dependent on age, sex, severity or duration of 153 rheumatoid arthritis. 154 In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a 155 reduction in joint pain or tenderness, an increase in range of motion in knee joints, 156 increased mobility as demonstrated by a reduction in walking time, and improvement in 157 capacity to perform activities of daily living impaired by the disease. 158 In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a 159 day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated 160 prematurely because of adverse events. Nineteen patients in the 1500 mg group 161 terminated prematurely because of adverse events. Most of these adverse events were 162 gastrointestinal events. 163 In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile 164 arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in 165 controlling the aforementioned measures of disease activity, but the frequency and 166 severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and 167 nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in 168 naproxen-treated patients than in those treated with aspirin or indomethacin. 169 In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, 170 morning stiffness and pain at rest. In double-blind studies the drug was shown to be as 171 effective as aspirin, but with fewer side effects. 172 In patients with acute gout, a favorable response to naproxen was shown by significant 173 clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, 174 as well as by relief of pain and tenderness. 175 Naproxen has been studied in patients with mild to moderate pain secondary to 176 postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and 177 dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen 178 and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown 179 by such measures as reduction of pain intensity scores, increase in pain relief scores, 180 decrease in numbers of patients requiring additional analgesic medication, and delay in 181 time to remedication. The analgesic effect has been found to last for up to 12 hours. 182 Naproxen may be used safely in combination with gold salts and/or corticosteroids; 183 however, in controlled clinical trials, when added to the regimen of patients receiving 184 corticosteroids, it did not appear to cause greater improvement over that seen with 185 corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been 186 adequately studied. When added to the regimen of patients receiving gold salts, naproxen 187 did result in greater improvement. Its use in combination with salicylates is not 188 recommended because there is evidence that aspirin increases the rate of excretion of 189 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 6 naproxen and data are inadequate to demonstrate that naproxen and aspirin produce 190 greater improvement over that achieved with aspirin alone. In addition, as with other 191 NSAIDs, the combination may result in higher frequency of adverse events than 192 demonstrated for either product alone. 193 In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 194 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX 195 (naproxen sodium) has been demonstrated to cause statistically significantly less gastric 196 bleeding and erosion than 3250 mg of aspirin. 197 Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 198 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted 199 comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and 200 osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These 201 studies indicated that EC-NAPROSYN and NAPROSYN showed no significant 202 differences in efficacy or safety and had similar prevalence of minor GI complaints. 203 Individual patients, however, may find one formulation preferable to the other. 204 Five hundred and fifty-three patients received EC-NAPROSYN during long-term open- 205 label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed 206 peptic ulcers and GI bleeds were similar to what has been historically reported for long- 207 term NSAID use. 208 Geriatric Patients: The hepatic and renal tolerability of long-term naproxen 209 administration was studied in two double blind clinical trials involving 586 patients. Of 210 the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 211 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice 212 daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and 213 renal function were noted in some patients, although there were no differences noted in 214 the occurrence of abnormal values among different age groups. 215 INDIVIDUALIZATION OF DOSAGE 216 Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and 217 ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic 218 differences that may affect onset of action. Onset of pain relief can begin within 30 219 minutes in patients taking naproxen sodium and within 1 hour in patients taking 220 naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the 221 stomach, the absorption of the drug is delayed compared to the other naproxen 222 formulations (see CLINICAL PHARMACOLOGY). 223 The recommended strategy for initiating therapy is to choose a formulation and a starting 224 dose likely to be effective for the patient and then adjust the dosage based on observation 225 of benefit and/or adverse events. A lower dose should be considered in patients with renal 226 or hepatic impairment or in elderly patients (see PRECAUTIONS). 227 Analgesia/Dysmenorrhea/Bursitis and Tendinitis: Because the sodium salt of naproxen 228 is more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the 229 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 7 management of acute painful conditions when prompt onset of pain relief is desired. The 230 recommended starting dose is 550 mg followed by 550 mg every 12 hours or 275 mg 231 every 6 to 8 hours, as required. The initial total daily dose should not exceed 1375 mg of 232 naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen 233 sodium. NAPROSYN may also be used for treatment of acute pain and dysmenorrhea. 234 EC-NAPROSYN is not recommended for initial treatment of acute pain because 235 absorption of naproxen is delayed compared to other naproxen-containing products (see 236 CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). 237 Acute Gout: The recommended starting dose is 750 mg of NAPROSYN followed by 250 238 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting 239 dose of 825 mg followed by 275 mg every 8 hours as needed. EC-NAPROSYN is not 240 recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). 241 Osteoarthritis/Rheumatoid Arthritis/Ankylosing Spondylitis: The recommended dose of 242 naproxen is NAPROSYN or NAPROSYN Suspension 250 mg, 375 mg or 500 mg taken 243 twice daily (morning and evening) or EC-NAPROSYN 375 mg or 500 mg taken twice 244 daily. Naproxen sodium may also be used (see DOSAGE AND ADMINISTRATION). 245 During long-term administration the dose of naproxen may be adjusted up or down 246 depending on the clinical response of the patient. A lower daily dose may suffice for 247 long-term administration. In patients who tolerate lower doses well, the dose may be 248 increased to 1500 mg per day for up to 6 months when a higher level of anti- 249 inflammatory/analgesic activity is required. When treating patients with naproxen 1500 250 mg/day (as NAPROSYN or 1650 mg of ANAPROX), the physician should observe 251 sufficient increased clinical benefit to offset the potential increased risk. The morning and 252 evening doses do not have to be equal in size and administration of the drug more 253 frequently than twice daily does not generally make a difference in response (see 254 CLINICAL PHARMACOLOGY). 255 Juvenile Arthritis: The use of NAPROSYN Suspension allows for more flexible dose 256 titration. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen 257 similar to those seen in adults taking 500 mg of naproxen (see CLINICAL 258 PHARMACOLOGY). 259 The recommended total daily dose is approximately 10 mg/kg given in two divided doses 260 (ie, 5 mg/kg given twice a day) (see DOSAGE AND ADMINISTRATION). 261 INDICATIONS AND USAGE 262 Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 263 NAPROSYN Suspension is indicated: 264 • For the relief of the signs and symptoms of rheumatoid arthritis 265 • For the relief of the signs and symptoms of osteoarthritis 266 • For the relief of the signs and symptoms of ankylosing spondylitis 267 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 8 • For the relief of the signs and symptoms of juvenile arthritis 268 Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis 269 in order to obtain the maximum dosage flexibility based on the patient’s weight. 270 Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is 271 also indicated: 272 • For relief of the signs and symptoms of tendinitis 273 • For relief of the signs and symptoms of bursitis 274 • For relief of the signs and symptoms of acute gout 275 • For the management of pain 276 • For the management of primary dysmenorrhea 277 EC-NAPROSYN is not recommended for initial treatment of acute pain because the 278 absorption of naproxen is delayed compared to absorption from other naproxen- 279 containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND 280 ADMINISTRATION). 281 CONTRAINDICATIONS 282 All naproxen products are contraindicated in patients who have had allergic reactions to 283 prescription as well as to over-the-counter products containing naproxen. It is also 284 contraindicated in patients in whom aspirin or other nonsteroidal anti- 285 inflammatory/analgesic drugs induce the syndrome of asthma, rhinitis, and nasal polyps. 286 Both types of reactions have the potential of being fatal. Anaphylactoid reactions to 287 naproxen, whether of the true allergic type or the pharmacologic idiosyncratic (eg, aspirin 288 hypersensitivity syndrome) type, usually but not always occur in patients with a known 289 history of such reactions. Therefore, careful questioning of patients for such things as 290 asthma, nasal polyps, urticaria, and hypotension associated with nonsteroidal anti- 291 inflammatory drugs before starting therapy is important. In addition, if such symptoms 292 occur during therapy, treatment should be discontinued (see WARNINGS: Anaphylactoid 293 Reactions and PRECAUTIONS: Preexisting Asthma). 294 WARNINGS 295 Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation: 296 Serious gastrointestinal toxicity such as bleeding, ulceration and perforation of the 297 stomach, small intestine or large intestine, can occur at any time, with or without warning 298 symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). 299 Minor upper gastrointestinal problems, such as dyspepsia, are common and may also 300 occur at any time during NSAID therapy. Therefore, physicians and patients should 301 remain alert for ulceration and bleeding, even in the absence of previous GI tract 302 symptoms (see PRECAUTIONS: Hematological Effects). Patients should be informed 303 about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. 304 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 9 The utility of periodic laboratory monitoring has not been demonstrated, nor has it been 305 adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event 306 on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross 307 bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of 308 patients treated for 3 to 6 months and in about 2% to 4% of patients treated for 1 year. 309 These trends continue, thus increasing the likelihood of developing a serious GI event at 310 some time during the course of therapy. However, even short-term therapy is not without 311 risk. 312 NSAIDs should be prescribed with extreme caution in patients with a prior history of 313 ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are 314 in elderly or debilitated patients and therefore special care should be taken in treating this 315 population. To minimize the potential risk for an adverse GI event, the lowest 316 effective dose should be used for the shortest possible duration. For high-risk patients, 317 alternate therapies that do not involve NSAIDs should be considered. 318 Studies have shown that patients with a prior history of peptic ulcer disease and/or 319 gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold risk for 320 developing a GI bleed than patients with neither of these risk factors. In addition to a past 321 history of ulcer disease, pharmacoepidemiological studies have identified several other 322 co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: 323 treatment with oral corticosteroids, treatment with anticoagulants, longer duration of 324 NSAID therapy, smoking, alcoholism, older age, and poor general health status. 325 Anaphylactoid Reactions: As with other NSAIDs, anaphylactoid reactions may occur in 326 patients without known prior exposure to naproxen. Naproxen should not be given to 327 patients with the aspirin triad. This symptom complex typically occurs in asthmatic 328 patients who experience rhinitis with or without nasal polyps, or who exhibit severe, 329 potentially fatal bronchospasm after taking aspirin or other NSAIDs (see 330 CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help 331 should be sought in cases where an anaphylactoid reaction occurs. 332 Advanced Renal Disease: In cases with advanced kidney disease, treatment with 333 naproxen is not recommended. If NSAID therapy, however, must be initiated, close 334 monitoring of the patient’s kidney function is advisable (see PRECAUTIONS: Renal 335 Effects). 336 Pregnancy: In late pregnancy, as with other NSAIDs, naproxen should be avoided 337 because it may cause premature closure of the ductus arteriosus. 338 PRECAUTIONS 339 General: NAPROXEN-CONTAINING PRODUCTS SUCH AS NAPROSYN, EC- 340 NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, 341 AND OTHER NAPROXEN PRODUCTS SHOULD NOT BE USED 342 CONCOMITANTLY SINCE THEY ALL CIRCULATE IN THE PLASMA AS 343 THE NAPROXEN ANION. 344 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 10 Naproxen cannot be expected to substitute for corticosteroids or to treat corticosteroid 345 insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. 346 Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a 347 decision is made to discontinue corticosteroids and the patient should be observed closely 348 for any evidence of adverse effects, including adrenal insufficiency and exacerbation of 349 symptoms of arthritis. 350 Patients with initial hemoglobin values of 10 g or less who are to receive long-term 351 therapy should have hemoglobin values determined periodically. 352 The antipyretic and anti-inflammatory activities of the drug may reduce fever and 353 inflammation, thus diminishing their utility as diagnostic signs in detecting complications 354 of presumed noninfectious, noninflammatory painful conditions. 355 Because of adverse eye findings in animal studies with drugs of this class, it is 356 recommended that ophthalmic studies be carried out if any change or disturbance in 357 vision occurs. 358 Hepatic Effects: As with other nonsteroidal anti-inflammatory drugs, borderline 359 elevations of one or more liver tests may occur in up to 15% of patients. These 360 abnormalities may progress, may remain essentially unchanged, or may be transient with 361 continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver 362 dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or 363 SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. A patient 364 with symptoms and/or signs suggesting liver dysfunction or in whom an abnormal liver 365 test has occurred, should be evaluated for evidence of the development of more severe 366 hepatic reaction while on therapy with naproxen. Severe hepatic reactions, including 367 jaundice and cases of fatal hepatitis, have been reported with naproxen as with other 368 nonsteroidal anti-inflammatory drugs. Although such reactions are rare, if abnormal liver 369 tests persist or worsen, if clinical signs and symptoms consistent with liver disease 370 develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), naproxen 371 should be discontinued. 372 Renal Effects: Caution should be used when initiating treatment with naproxen in 373 patients with considerable dehydration. It is advisable to rehydrate patients first and then 374 start therapy with naproxen. Caution is also recommended in patients with pre-existing 375 kidney disease (see WARNINGS: Advanced Renal Disease). 376 As with other nonsteroidal anti-inflammatory drugs, long-term administration of 377 naproxen to animals has resulted in renal papillary necrosis and other abnormal renal 378 pathology. In humans, there have been reports of impaired renal function, renal failure, 379 acute interstitial nephritis, hematuria, proteinuria, renal papillary necrosis, and 380 occasionally nephrotic syndrome associated with naproxen-containing products and other 381 NSAIDs since they have been marketed. 382 A second form of renal toxicity has been seen in patients taking naproxen as well as other 383 nonsteroidal anti-inflammatory drugs. In patients with prerenal conditions leading to a 384 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 11 reduction in renal blood flow or blood volume, where the renal prostaglandins have a 385 supportive role in the maintenance of renal perfusion, caution should be observed since 386 administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent 387 reduction in prostaglandin formation and may precipitate overt renal decompensation or 388 failure. Patients at greatest risk of this reaction are those with impaired renal function, 389 hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and 390 ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory 391 therapy is typically followed by recovery to the pretreatment state. 392 Naproxen and its metabolites are eliminated primarily by the kidneys; therefore, the drug 393 should be used with caution in such patients and the monitoring of serum creatinine 394 and/or creatinine clearance is advised. A reduction in daily dosage should be considered 395 to avoid the possibility of excessive accumulation of naproxen metabolites in these 396 patients. Naproxen-containing products are not recommended for use in patients with 397 moderate to severe and severe renal impairment (creatinine < 30 ml/min). 398 Chronic alcoholic liver disease and probably other diseases with decreased or abnormal 399 plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the 400 plasma concentration of unbound naproxen is increased. Caution is advised when high 401 doses are required and some adjustment of dosage may be required in these patients. It is 402 prudent to use the lowest effective dose. 403 Studies indicate that although total plasma concentration of naproxen is unchanged, the 404 unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when 405 high doses are required and some adjustment of dosage may be required in elderly 406 patients. As with other drugs used in the elderly, it is prudent to use the lowest effective 407 dose. 408 Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, 409 including naproxen. This may be due to fluid retention, GI loss, or an incompletely 410 described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, 411 including naproxen, should have their hemoglobin or hematocrit checked if they exhibit 412 any signs or symptoms of anemia. 413 All drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent 414 with platelet function and vascular responses to bleeding. 415 NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in 416 some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of 417 shorter duration, and reversible. Naproxen does not generally affect platelet counts, 418 prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving naproxen 419 who may be adversely affected by alterations in platelet function, such as those with 420 coagulation disorders or patients receiving anticoagulants, should be carefully monitored. 421 Fluid Retention and Edema: Peripheral edema has been observed in some patients 422 receiving naproxen. Since each ANAPROX or ANAPROX DS tablet contains 25 mg or 423 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of 424 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 12 NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of naproxen) 425 of sodium, this should be considered in patients whose overall intake of sodium must be 426 severely restricted. For these reasons, ANAPROX, ANAPROX DS and NAPROSYN 427 Suspension should be used with caution in patients with fluid retention, hypertension or 428 heart failure. 429 Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of 430 aspirin in patients with aspirin-sensitive asthma has been associated with severe 431 bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, 432 between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such 433 aspirin-sensitive patients, naproxen should not be administered to patients with this form 434 of aspirin sensitivity and should be used with caution in patients with preexisting asthma. 435 Information for Patients: Naproxen, in NAPROSYN, EC-NAPROSYN, ANAPROX, 436 ANAPROX DS and NAPROSYN Suspension can cause discomfort and, rarely, more 437 serious side effects, such as gastrointestinal bleeding, which may result in hospitalization 438 and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur 439 without warning symptoms, patients should be alert for the signs and symptoms of 440 ulcerations and bleeding, and should ask for medical advice when observing any 441 indicative signs or symptoms. Patients should be apprised of the importance of this 442 follow-up (see WARNINGS: Gastrointestinal (GI) Effects-Risk of GI Ulceration, 443 Bleeding, and Perforation). 444 Patients should promptly report signs or symptoms of gastrointestinal ulceration or 445 bleeding, skin rash, unexplained weight gain or edema to their physicians. 446 Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, 447 nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu- 448 like” symptoms). If these occur, patients should be instructed to stop therapy and seek 449 immediate medical therapy. 450 Patients should also be instructed to seek immediate emergency help in the case of an 451 anaphylactoid reaction (see WARNINGS). 452 In late pregnancy, naproxen, in NAPROSYN, EC-NAPROSYN, ANAPROX, 453 ANAPROX DS, and NAPROSYN SUSPENSION, should be avoided because it may 454 cause premature closure of the ductus arteriosus. 455 Caution should be exercised by patients whose activities require alertness if they 456 experience drowsiness, dizziness, vertigo or depression during therapy with naproxen. 457 Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without 458 warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. If 459 clinical signs and symptoms consistent with liver or renal disease develop, systemic 460 manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or 461 worsen, naproxen should be discontinued. 462 Drug Interactions: 463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 13 Aspirin: Concomitant administration of naproxen and aspirin is not recommended 464 because naproxen is displaced from its binding sites during the concomitant 465 administration of aspirin, resulting in lower plasma concentrations and peak plasma 466 levels. 467 Methotrexate: Caution should be used if naproxen is administered concomitantly with 468 methotrexate. Naproxen, naproxen sodium and other nonsteroidal anti-inflammatory 469 drugs have been reported to reduce the tubular secretion of methotrexate in an animal 470 model, possibly increasing the toxicity of methotrexate. 471 ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect 472 of ACE-inhibitors. The use of NSAIDs in patients who are receiving ACE inhibitors may 473 potentiate renal disease states (see PRECAUTIONS: Renal Effects). 474 Furosemide: Clinical studies, as well as postmarketing observations, have shown that 475 NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. 476 This response has been attributed to inhibition of renal prostaglandin synthesis. 477 Lithium: Inhibition of renal lithium clearance leading to increases in plasma lithium 478 concentrations has also been reported. The mean minimum lithium concentration 479 increased 15% and the renal clearance was decreased by approximately 20%. These 480 effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. 481 Thus, when NSAIDs and lithium are administered concurrently, patients should be 482 observed carefully for signs of lithium toxicity. 483 Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that 484 patients taking both drugs have a risk of serious GI bleeding that is higher than patients 485 taking either drug alone. No significant interactions have been observed in clinical 486 studies with naproxen and coumarin-type anticoagulants. However, caution is advised 487 since interactions have been seen with other nonsteroidal agents of this class. The free 488 fraction of warfarin may increase substantially in some subjects and naproxen interferes 489 with platelet function. 490 Other Information Concerning Drug Interactions: 491 Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for 492 interaction with other albumin-bound drugs such as coumarin-type anticoagulants, 493 sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously 494 receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed 495 for adjustment of dose if required. 496 Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the 497 antihypertensive effect of propranolol and other beta-blockers. 498 Probenecid given concurrently increases naproxen anion plasma levels and extends its 499 plasma half-life significantly. 500 Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid 501 therapy, concomitant administration of EC-NAPROSYN is not recommended. 502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 14 Drug/Laboratory Test Interactions: Naproxen may decrease platelet aggregation and 503 prolong bleeding time. This effect should be kept in mind when bleeding times are 504 determined. 505 The administration of naproxen may result in increased urinary values for 17-ketogenic 506 steroids because of an interaction between the drug and/or its metabolites with m-di- 507 nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements 508 (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy 509 with naproxen be temporarily discontinued 72 hours before adrenal function tests are 510 performed if the Porter-Silber test is to be used. 511 Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid 512 (5HIAA). 513 Carcinogenesis: A 2-year study was performed in rats to evaluate the carcinogenic 514 potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). 515 The maximum dose used was 0.28 times the systemic exposure to humans at the 516 recommended dose. No evidence of tumorigenicity was found. 517 Pregnancy: Teratogenic Effects: Pregnancy Category C. Reproduction studies have been 518 performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic 519 exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic 520 exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic 521 exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. 522 There are no adequate and well-controlled studies in pregnant women. Because animal 523 reproduction studies are not always predictive of human response, naproxen should not 524 be used during pregnancy unless clearly needed. 525 Nonteratogenic Effects: There is some evidence to suggest that when inhibitors of 526 prostaglandin synthesis are used to delay preterm labor there is an increased risk of 527 neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and 528 intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition 529 has been associated with persistent pulmonary hypertension, renal dysfunction and 530 abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs 531 of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use 532 during third trimester should be avoided. 533 Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit 534 prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and 535 decreased pup survival occurred. Naproxen-containing products are not recommended in 536 labor and delivery because, through its prostaglandin synthesis inhibitory effect, 537 naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus 538 increasing the risk of uterine hemorrhage. 539 Nursing Mothers: The naproxen anion has been found in the milk of lactating women at 540 a concentrations equivalent to approximately 1% of maximum naproxen concentration in 541 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 15 plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on 542 neonates, use in nursing mothers should be avoided. 543 Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 years 544 have not been established. Pediatric dosing recommendations for juvenile arthritis are 545 based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are 546 no adequate effectiveness or dose-response data for other pediatric conditions, but the 547 experience in juvenile arthritis and other use experience have established that single 548 doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND 549 ADMINISTRATION), with total daily dose not exceeding 15 mg/kg/day, are well 550 tolerated in pediatric patients over 2 years of age. 551 Geriatric Use: Studies indicate that although total plasma concentration of naproxen is 552 unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution 553 is advised when high doses are required and some adjustment of dosage may be required 554 in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest 555 effective dose. 556 Experience indicates that geriatric patients may be particularly sensitive to certain 557 adverse effects of nonsteroidal anti-inflammatory drugs. While age does not appear to be 558 an independent risk factor for the development of peptic ulceration and bleeding with 559 naproxen administration, elderly or debilitated patients seem to tolerate peptic ulceration 560 or bleeding less well when these events do occur. Most spontaneous reports of fatal GI 561 events are in the geriatric population (see WARNINGS). 562 Naproxen is known to be substantially excreted by the kidney, and the risk of toxic 563 reactions to this drug may be greater in patients with impaired renal function. Because 564 elderly patients are more likely to have decreased renal function, care should be taken in 565 dose selection, and it may be useful to monitor renal function. Geriatric patients may be 566 at a greater risk for the development of a form of renal toxicity precipitated by reduced 567 prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs 568 (see PRECAUTIONS: Renal Effects). 569 ADVERSE REACTIONS 570 Adverse reactions reported in controlled clinical trials in 960 patients treated for 571 rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients 572 treated chronically were reported 2 to 10 times more frequently than they were in short- 573 term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. 574 The most frequent complaints reported related to the gastrointestinal tract. 575 A clinical study found gastrointestinal reactions to be more frequent and more severe in 576 rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those 577 taking 750 mg naproxen (see CLINICAL PHARMACOLOGY). 578 In controlled clinical trials with about 80 pediatric patients and in well-monitored, open- 579 label studies with about 400 pediatric patients with juvenile arthritis treated with 580 naproxen, the incidence of rash and prolonged bleeding times were increased, the 581 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 16 incidence of gastrointestinal and central nervous system reactions were about the same, 582 and the incidence of other reactions were lower in pediatric patients than in adults. 583 In patients taking naproxen in clinical trials, the most frequently reported adverse 584 experiences in approximately 1 to 10% of patients are: 585 Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, 586 constipation, diarrhea, dyspepsia, stomatitis 587 Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo 588 Dermatologic: pruritus (itching) , skin eruptions, ecchymoses, sweating, purpura 589 Special Senses: tinnitus, visual disturbances, hearing disturbances 590 Cardiovascular: edema, palpitations 591 General: dyspnea, thirst 592 Incidence of reported reaction between 3% and 9%. Those reactions occurring in less 593 than 3% of the patients are unmarked. 594 In patients taking NSAIDs, the following adverse experiences have also been reported in 595 approximately 1 to 10% of patients. 596 Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI 597 ulcers (gastric/duodenal), vomiting 598 General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding 599 time, rashes 600 The following are additional adverse experiences reported in <1% of patients taking 601 naproxen during clinical trials and through post-marketing reports. Those adverse 602 reactions observed through post-marketing reports are italicized. 603 Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, 604 pyrexia (chills and fever) 605 Cardiovascular: congestive heart failure, vasculitis 606 Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice, 607 pancreatitis, vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal 608 ulceration, ulcerative stomatitis 609 Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, 610 agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia 611 Metabolic and Nutritional: hyperglycemia, hypoglycemia 612 Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, 613 malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction 614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 17 Respiratory: eosinophilic pneumonitis 615 Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema 616 multiforme, Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity 617 reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) 618 or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of 619 pseudoporphyria occur, treatment should be discontinued and the patient monitored. 620 Special Senses: hearing impairment 621 Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, 622 nephrotic syndrome, renal disease, renal failure, renal papillary necrosis 623 In patients taking NSAIDs, the following adverse experiences have also been reported in 624 <1% of patients. 625 Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death 626 Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, 627 myocardial infarction 628 Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, 629 hepatitis, eructation, liver failure 630 Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia 631 Metabolic and Nutritional: weight changes 632 Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, 633 tremors, convulsions, coma, hallucinations 634 Respiratory: asthma, respiratory depression, pneumonia 635 Dermatologic: exfoliative dermatitis 636 Special Senses: blurred vision, conjunctivitis 637 Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria 638 OVERDOSAGE 639 Significant naproxen overdosage may be characterized by lethargy, dizziness, 640 drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, 641 transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic 642 acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. 643 Hypertension, acute renal failure, respiratory depression, and coma may occur, but are 644 rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, 645 and may occur following an overdose. Because naproxen sodium may be rapidly 646 absorbed, high and early blood levels should be anticipated. A few patients have 647 experienced convulsions, but it is not clear whether or not these were drug-related. It is 648 not known what dose of the drug would be life threatening. The oral LD50 of the drug is 649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 18 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 650 mg/kg in dogs. 651 Patients should be managed by symptomatic and supportive care following a NSAID 652 overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma 653 concentration of naproxen because of the high degree of its protein binding. Emesis 654 and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic 655 cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or 656 following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may 657 not be useful due to high protein binding. 658 DOSAGE AND ADMINISTRATION 659 Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis: 660 NAPROSYN 250 mg or 375 mg or 500 mg twice daily twice daily twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp) or 375 mg (15 mL/3 tsp) or 500 mg (20 mL/4 tsp) twice daily twice daily twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be 661 broken, crushed or chewed during ingestion. 662 During long-term administration, the dose of naproxen may be adjusted up or down 663 depending on the clinical response of the patient. A lower daily dose may suffice for 664 long-term administration. The morning and evening doses do not have to be equal in size 665 and the administration of the drug more frequently than twice daily is not necessary. 666 In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 667 mg per day for limited periods of up to 6 months when a higher level of anti- 668 inflammatory/analgesic activity is required. When treating such patients with naproxen 669 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset 670 the potential increased risk (see CLINICAL PHARMACOLOGY and 671 INDIVIDUALIZATION OF DOSAGE). 672 Geriatric Patients: Studies indicate that although total plasma concentration of naproxen 673 is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. 674 Caution is advised when high doses are required and some adjustment of dosage may be 675 required in elderly patients. As with other drugs used in the elderly, it is prudent to use 676 the lowest effective dose. 677 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 19 Juvenile Arthritis: The recommended total daily dose of naproxen is approximately 10 678 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked 679 in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN 680 Suspension. The following table may be used as a guide for dosing of NAPROSYN 681 Suspension: 682 Patient’s Weight Dose Administered as 683 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 684 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 685 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily 686 Management of Pain, Primary Dysmenorrhea and Acute Tendonitis and Bursitis: The 687 recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX 688 DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The 689 initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the 690 total daily dose should not exceed 1100 mg of naproxen sodium. NAPROSYN may also 691 be used but EC-NAPROSYN is not recommended for initial treatment of acute pain 692 because absorption of naproxen is delayed compared to other naproxen-containing 693 products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE and 694 INDIVIDUALIZATION OF DOSAGE). 695 Acute Gout: The recommended starting dose is 750 mg of NAPROSYN followed by 250 696 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting 697 dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not 698 recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). 699 HOW SUPPLIED 700 NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on 701 one side and scored on the other. Packaged in light-resistant bottles of 100. 702 100’s (bottle): NDC 0004-6313-01. 703 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light- 704 resistant bottles of 100 and 500. 705 100’s (bottle): NDC 0004-6314-01; 500’s (bottle): NDC 0004-6314-14. 706 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on 707 the other. Packaged in light-resistant bottles of 100 and 500. 708 100’s (bottle): NDC 0004-6316-01; 500’s (bottle): NDC 0004-6316-14. 709 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant 710 containers. 711 NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 712 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28). 713 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 20 Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). Dispense 714 in light-resistant containers. 715 EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, capsule-shaped, imprinted 716 with EC-NAPROSYN on one side and 375 on the other. Packaged in light-resistant 717 bottles of 100. 718 100’s (bottle): NDC 0004-6415-01. 719 500 mg: white, capsule-shaped, imprinted with EC-NAPROSYN on one side and 500 on 720 the other. Packaged in light-resistant bottles of 100. 721 100’s (bottle): NDC 0004-6416-01. 722 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant 723 containers. 724 ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with 725 NPS-275 on one side. Packaged in bottles of 100. 726 100’s (bottle): NDC 0004-6202-01. 727 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 728 ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong-shaped, engraved 729 with NPS 550 on one side and scored on both sides. Packaged in bottles of 100 and 500. 730 100’s (bottle): NDC 0004-6203-01; 500’s (bottle): NDC 0004-6203-14. 731 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 732 * ALEVE is a registered trademark of Bayer-Roche L.L.C. 733 734 Distributed by: 735 736 XXXXXXXX 737 Revised: Month/Year 738 Copyright © 1999-2004 by Roche Laboratories Inc. All rights reserved. 739 740 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:07.232912	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/17581s99,100,18164s50,51,18965s9,10,20067s4,6lbl.pdf', 'application_number': 18965, 'submission_type': 'SUPPL ', 'submission_number': 10}
11,380	elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing PROZAC. Do not use thioridazine within 5 weeks of discontinuing PROZAC (4.2, 5.11, 7.7, 7.8) 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PROZAC safely and effectively. See full prescribing information for PROZAC. PROZAC (fluoxetine capsules) for oral use PROZAC (fluoxetine delayed-release capsules) for oral use Initial U.S. Approval: 1987 WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1). • Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1). When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax. --------------------------- RECENT MAJOR CHANGES ------------------------- Warnings and Precautions: Angle-Closure Glaucoma (5.8) 07/2014 ---------------------------- INDICATIONS AND USAGE -------------------------- PROZAC® is a selective serotonin reuptake inhibitor indicated for: • Acute and maintenance treatment of Major Depressive Disorder (MDD) (1) • Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) (1) • Acute and maintenance treatment of Bulimia Nervosa (1) • Acute treatment of Panic Disorder, with or without agoraphobia (1) PROZAC and olanzapine in combination for treatment of: • Acute Depressive Episodes Associated with Bipolar I Disorder (1) • Treatment Resistant Depression (1) ------------------------DOSAGE AND ADMINISTRATION ---------------------- Indication Adult Pediatric MDD (2.1) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD (2.2) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa (2.3) 60 mg/day in am Panic Disorder (2.4) 10 mg/day (initial dose) Depressive Episodes Associated with Bipolar I Disorder (2.5) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) Oral in combination with olanzapine: 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) Treatment Resistant Depression (2.6) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) • A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.7) • Dosing with PROZAC Weekly capsules - initiate 7 days after the last daily dose of PROZAC 20 mg (2.1) PROZAC and olanzapine in combination: • Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults (2.5, 2.6) • Safety of the coadministration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17 (2.5) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- • Pulvules: 10 mg, 20 mg, 40 mg (3) • Weekly capsules: 90 mg (3) ------------------------------- CONTRAINDICATIONS ----------------------------- • Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with PROZAC or within 5 weeks of stopping treatment with PROZAC. Do not use PROZAC within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start PROZAC in a patient who is being treated with linezolid or intravenous methylene blue (4.1) • Pimozide: Do not use. Risk of QT prolongation and drug interaction (4.2, 5.11, 7.7, 7.8) • Thioridazine: Do not use. Risk of QT interval prolongation and • When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax (4) ------------------------ WARNINGS AND PRECAUTIONS ---------------------- • Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Monitor for clinical worsening and suicidal thinking and behavior (5.1) • Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including PROZAC, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort). If such symptoms occur, discontinue PROZAC and initiate supportive treatment. If concomitant use of PROZAC with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. (5.2) • Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena (5.3) • Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4) • Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.5) • Altered Appetite and Weight: Significant weight loss has occurred (5.6) • Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.7) • Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.8) • Hyponatremia: Has been reported with PROZAC in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing if symptomatic hyponatremia occurs (5.9) • Anxiety and Insomnia: May occur (5.10) • QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with PROZAC use. Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation (4.2, 5.11, 7.7, 7.8, 10.1) • Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery (5.13) • Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks (5.14) • PROZAC and Olanzapine in Combination: When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax (5.16) • Dosage adjustments should be made with the individual -------------------------------ADVERSE REACTIONS ----------------------------- components according to efficacy and tolerability (2.5, 2.6) Most common adverse reactions (≥5% and at least twice that for • Fluoxetine monotherapy is not indicated for the treatment of placebo) associated with: Depressive Episodes associated with Bipolar I Disorder or treatment resistant depression (2.5, 2.6) Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1) PROZAC and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for Symbyax (6) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800 FDA-1088 or www.fda.gov/medwatch ------------------------------- DRUG INTERACTIONS ----------------------------- • Monoamine Oxidase Inhibitors (MAOIs): (2.9, 2.10, 4.1, 5.2) • Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7) • Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with PROZAC or when PROZAC has been recently discontinued (5.2, 7.7) • CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2) • Benzodiazepines: Diazepam – increased t½, alprazolam - further psychomotor performance decrement due to increased levels (7.7) • Antipsychotics: Potential for elevation of haloperidol and clozapine levels (7.7) • Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.7) • Serotonergic Drugs: (2.9, 2.10, 4.1, 5.2) • Drugs that Interfere with Hemostasis (e.g. NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding (7.4) • Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations (7.6, 7.7) • Olanzapine: When used in combination with PROZAC, also refer to the Drug Interactions section of the package insert for Symbyax (7.7) • Drugs that Prolong the QT Interval: Do not use Prozac with thioridazine or pimozide. Use with caution in combination with other drugs that prolong the QT interval (4.2, 5.11, 7.7, 7.8) ------------------------USE IN SPECIFIC POPULATIONS---------------------- • Pregnancy: PROZAC should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus (8.1) • Nursing Mothers: Breast feeding is not recommended (8.3) • Pediatric Use: Safety and effectiveness of PROZAC in patients <8 years of age with Major Depressive Disorder and <7 years of age with OCD have not been established. Safety and effectiveness of PROZAC and olanzapine in combination in patients <10 years of age for depressive episodes associated with Bipolar I Disorder have not been established. (8.4) • Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis (8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved Medication Guide. Revised: 00/0000 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SUICIDAL THOUGHTS AND BEHAVIORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Major Depressive Disorder 2.2 Obsessive Compulsive Disorder 2.3 Bulimia Nervosa 2.4 Panic Disorder 2.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder 2.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression 2.7 Dosing in Specific Populations 2.8 Discontinuation of Treatment 2.9 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders 2.10 Use of PROZAC with Other MAOIs such as Linezolid or Methylene Blue 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Monoamine Oxidase Inhibitors (MAOIs) 4.2 Other Contraindications 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults 5.2 Serotonin Syndrome 5.3 Allergic Reactions and Rash 5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 5.5 Seizures 5.6 Altered Appetite and Weight 5.7 Abnormal Bleeding 5.8 Angle-Closure Glaucoma 5.9 Hyponatremia 5.10 Anxiety and Insomnia 5.11 QT Prolongation 5.12 Use in Patients with Concomitant Illness 5.13 Potential for Cognitive and Motor Impairment 5.14 Long Elimination Half-Life 5.15 Discontinuation Adverse Reactions 5.16 PROZAC and Olanzapine in Combination 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Other Reactions 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Monoamine Oxidase Inhibitors (MAOI) 7.2 CNS Acting Drugs 7.3 Serotonergic Drugs 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) 7.5 Electroconvulsive Therapy (ECT) 7.6 Potential for Other Drugs to affect PROZAC 7.7 Potential for PROZAC to affect Other Drugs 7.8 Drugs that Prolong the QT Interval 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 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.3 Dependence 10 OVERDOSAGE 10.1 Human Experience 10.2 Animal Experience 10.3 Management of Overdose 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Specific Populations 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Major Depressive Disorder 14.2 Obsessive Compulsive Disorder 14.3 Bulimia Nervosa 14.4 Panic Disorder 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 17.1 General Information 17.2 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults 17.3 Serotonin Syndrome 17.4 Allergic Reactions and Rash 17.5 Abnormal Bleeding 17.6 Angle-Closure Glaucoma 17.7 Hyponatremia 17.8 QT Prolongation 17.9 Potential for Cognitive and Motor Impairment 17.10 Use of Concomitant Medications 17.11 Discontinuation of Treatment 17.12 Use in Specific Populations Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 FULL PRESCRIBING INFORMATION WARNING: SUICIDAL THOUGHTS AND BEHAVIORS • Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)]. • In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)]. • PROZAC is not approved for use in children less than 7 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax. 1 INDICATIONS AND USAGE PROZAC® is indicated for the treatment of: • Acute and maintenance treatment of Major Depressive Disorder [see Clinical Studies (14.1)]. • Acute and maintenance treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2)]. • Acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)]. • Acute treatment of Panic Disorder, with or without agoraphobia [see Clinical Studies (14.4)]. PROZAC and Olanzapine in Combination is indicated for the treatment of: • Acute treatment of depressive episodes associated with Bipolar I Disorder. • Treatment resistant depression (Major Depressive Disorder in patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode). PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder or the treatment of treatment resistant depression. When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax® . 2 DOSAGE AND ADMINISTRATION 2.1 Major Depressive Disorder Initial Treatment Adult — Initiate PROZAC 20 mg/day orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon).The maximum fluoxetine dose should not exceed 80 mg/day. In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases [see Clinical Studies (14.1)]. Pediatric (children and adolescents) — Initiate PROZAC 10 or 20 mg/day. After 1 week at 10 mg/day, increase the dose to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement is observed. In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies (14.1)]. All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. Periodically reassess to determine the need for maintenance treatment. Weekly Dosing — Initiate PROZAC Weekly capsules 7 days after the last daily dose of PROZAC 20 mg [see Clinical Pharmacology (12.3)]. If satisfactory response is not maintained with PROZAC Weekly, consider reestablishing a daily dosing regimen [see Clinical Studies (14.1)]. Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Drug Interactions (7.7)]. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 2.2 Obsessive Compulsive Disorder Initial Treatment Adult — Initiate PROZAC 20 mg/day, orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Administer doses above 20 mg/day once daily in the morning or twice daily(i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Pediatric (children and adolescents) — In adolescents and higher weight children, initiate treatment with a dose of 10 mg/day. After 2 weeks, increase the dose to 20 mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, initiate treatment with a dose of 10 mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)]. Periodically reassess to determine the need for treatment. 2.3 Bulimia Nervosa Initial Treatment — Administer PROZAC 60 mg/day in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo [see Clinical Studies (14.3)]. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Periodically reassess to determine the need for maintenance treatment. 2.4 Panic Disorder Initial Treatment — Initiate treatment with PROZAC 10 mg/day. After one week, increase the dose to 20 mg/day. Consider a dose increase after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.4)]. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. Periodically reassess to determine the need for continued treatment. 2.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adult — Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Make dosage adjustments, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. Periodically re-examine the need for continued pharmacotherapy. Children and adolescents (10 -17 years of age) — Administer olanzapine and fluoxetine combination once daily in the evening, generally beginning with 2.5 mg of olanzapine and 20 mg of fluoxetine. Make dosage adjustments, if indicated, according to efficacy and tolerability. Safety of co-administration of doses above 12 mg of olanzapine with 50 mg of fluoxetine has not been evaluated in pediatric clinical studies. Periodically re-examine the need for continued pharmacotherapy. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Adjust dosage, if indicated, with the individual components according to efficacy and tolerability. Table 1: Approximate Dose Correspondence Between Symbyax 1 and the Combination of PROZAC and Olanzapine For Use in Combination Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Symbyax (mg/day) Olanzapine (mg/day) PROZAC (mg/day) 3 mg olanzapine/25 mg fluoxetine 2.5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 1 Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of PROZAC and olanzapine. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. 2.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Adjust dosage, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 20 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Adjust dosage, if indicated, with the individual components according to efficacy and tolerability. Periodically re-examine the need for continued pharmacotherapy. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. PROZAC monotherapy is not indicated for the treatment of treatment resistant depression (Major Depressive Disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode). 2.7 Dosing in Specific Populations Treatment of Pregnant Women — W hen treating pregnant women with PROZAC, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations (8.1)]. Geriatric — Consider a lower or less frequent dosage for the elderly [see Use in Specific Populations (8.5)]. Hepatic Impairment — As with many other medications, use a lower or less frequent dosage in patients with hepatic impairment [see Clinical Pharmacology (12.4) and Use in Specific Populations (8.6)]. Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology (12.4) and Warnings and Precautions (5.12)]. PROZAC and Olanzapine in Combination — Use a starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Titrate slowly and adjust dosage as needed in patients who exhibit a combination of factors that may slow metabolism. PROZAC and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 10 years of age [see Warnings and Precautions (5.16) and Drug Interactions (7.7)]. 2.8 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.15)]. 2.9 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 PROZAC. Conversely, at least 5 weeks should be allowed after stopping PROZAC before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)]. 2.10 Use of PROZAC with Other MAOIs such as Linezolid or Methylene Blue Do not start PROZAC in a patient who is being treated with linezolid or intravenous methylene blue because there is an 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 (4.1)]. In some cases, a patient already receiving PROZAC therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 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, PROZAC should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with PROZAC may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)]. 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 PROZAC is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)]. 3 DOSAGE FORMS AND STRENGTHS • 10 mg Pulvule is an opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body • 20 mg Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body • 40 mg Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body • 90 mg Prozac Weekly™ Capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body 4 CONTRAINDICATIONS When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with PROZAC or within 5 weeks of stopping treatment with PROZAC is contraindicated because of an increased risk of serotonin syndrome. The use of PROZAC within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.9) and Warnings and Precautions (5.2)]. Starting PROZAC 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 Dosage and Administration (2.10) and Warnings and Precautions (5.2)]. 4.2 Other Contraindications The use of PROZAC is contraindicated with the following: • Pimozide [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)] • Thioridazine [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)] Pimozide and thioridazine prolong the QT interval. PROZAC can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. PROZAC can also prolong the QT interval. 5 WARNINGS AND PRECAUTIONS When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults 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 versus placebo), however, were relatively stable within age strata Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2. Table 2: Suicidality per 1000 Patients Treated 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. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.15)]. 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 PROZAC should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. It should be noted that PROZAC is approved in the pediatric population for Major Depressive Disorder and Obsessive Compulsive Disorder; and PROZAC in combination with olanzapine for the acute treatment of depressive episodes associated with Bipolar I Disorder. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including PROZAC, 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 PROZAC with MAOIs intended to treat psychiatric disorders is contraindicated. PROZAC 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 PROZAC. PROZAC Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) and Dosage and Administration (2.9, 2.10)]. If concomitant use of PROZAC with other serotonergic drugs, i.e., 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 PROZAC and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.3 Allergic Reactions and Rash In US fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely. In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of PROZAC, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions. Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom. Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, PROZAC should be discontinued. 5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 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. W hether any of the symptoms described for clinical worsening and suicide risk 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 PROZAC and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions section of the package insert for Symbyax]. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with PROZAC and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see Use in Specific Populations (8.4)]. In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with PROZAC and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In US PROZAC clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)]. 5.5 Seizures In US placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with PROZAC and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In US PROZAC clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. PROZAC should be introduced with care in patients with a history of seizures. 5.6 Altered Appetite and Weight Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with PROZAC. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with PROZAC and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with PROZAC and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with PROZAC because of anorexia or weight loss [see Use in Specific Populations (8.4)]. In US placebo-controlled clinical trials for OCD, 17% of patients treated with PROZAC and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with PROZAC because of anorexia [see Use in Specific Populations (8.4)]. In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with PROZAC 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with PROZAC 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy. 5.7 Abnormal Bleeding SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.4)]. 5.8 Angle-Closure Glaucoma Angle-Closure Glaucoma — The pupillary dilation that occurs following use of many antidepressant drugs including Prozac may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.9 Hyponatremia Hyponatremia has been reported during treatment with SNRIs and SSRIs, including PROZAC. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when PROZAC was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of PROZAC should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.10 Anxiety and Insomnia In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with PROZAC and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with PROZAC and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with PROZAC and in 7% of patients treated with placebo. In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with PROZAC 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with PROZAC 60 mg and in 9% and 5% of patients treated with placebo. Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5]. 5.11 QT Prolongation Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with PROZAC. PROZAC should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). PROZAC is primarily metabolized by CYP2D6 [see Contraindications (4.2), Drug Interactions (7.7, 7.8), Overdose (10.1), and Clinical Pharmacology (12.3)]. Pimozide and thioridazine are contraindicated for use with PROZAC. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 6 antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions (7.7, 7.8) and Clinical Pharmacology (12.3)]. Consider ECG assessment and periodic ECG monitoring if initiating treatment with PROZAC in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing PROZAC and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. 5.12 Use in Patients with Concomitant Illness Clinical experience with PROZAC in patients with concomitant systemic illness is limited. Caution is advisable in using PROZAC in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received PROZAC in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. Glycemic Control — In patients with diabetes, PROZAC may alter glycemic control. Hypoglycemia has occurred during therapy with PROZAC, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with PROZAC is instituted or discontinued. 5.13 Potential for Cognitive and Motor Impairment As with any CNS-active drug, PROZAC has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. 5.14 Long Elimination Half-Life Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see Clinical Pharmacology (12.3)]. 5.15 Discontinuation Adverse Reactions During marketing of PROZAC, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with PROZAC. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. 5.16 PROZAC and Olanzapine in Combination When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. ADVERSE REACTION The following adverse reactions are discussed in more detail in other sections of the labeling: • Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)] • Serotonin Syndrome [see Warnings and Precautions (5.2)] • Allergic Reactions and Rash [see Warnings and Precautions (5.3)] • Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions (5.4)] • Seizures [see Warnings and Precautions (5.5)] • Altered Appetite and Weight [see Warnings and Precautions (5.6)] • Abnormal Bleeding [see Warnings and Precautions (5.7)] • Angle-Closure Glaucoma [see Warnings and Precautions (5.8)] • Hyponatremia [see Warnings and Precautions (5.9)] • Anxiety and Insomnia [see Warnings and Precautions (5.10)] • QT Prolongation [see Warnings and Precautions (5.11)] • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13)] • Discontinuation Adverse Reactions [see Warnings and Precautions (5.15)] Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 When using PROZAC and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of PROZAC have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered PROZAC in panic clinical trials. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use of PROZAC (incidence of at least 5% for PROZAC and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, OCD, and bulimia in US controlled clinical trials and Panic Disorder in US plus non-US controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with PROZAC and with incidence greater than placebo who participated in US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3. Table 3: Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1,2 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Reaction PROZAC (N=1728) Placebo (N=975) PROZAC (N=266) Placebo (N=89) PROZAC (N=450) Placebo (N=267) PROZAC (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 - 2 1 1 - Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 - 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn - - 7 - 11 - 1 - Skin and Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Appendages Sweating 8 3 7 - 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence3 2 - - - 7 - 1 - Abnormal ejaculation3 - - 7 - 7 - 2 1 1 Incidence less than 1%. 2 Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. 3 Denominator used was for males only (N=690 PROZAC Major Depressive Disorder; N=410 placebo Major Depressive Disorder; N=116 PROZAC OCD; N=43 placebo OCD; N=14 PROZAC bulimia; N=1 placebo bulimia; N=162 PROZAC panic; N=121 placebo panic). Table 4: Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1,2 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Reaction PROZAC (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 - Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 1 Incidence less than 1%. 2 Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 5 lists the adverse reactions associated with discontinuation of PROZAC treatment (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials. Table 5: Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) - Anxiety (2%) - Anxiety (2%) - - - Insomnia (2%) - - Nervousness (1%) - - Nervousness (1%) - - Rash (1%) - - 1 Includes US Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials. Other adverse reactions in pediatric patients (children and adolescents) — Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected. Reactions observed in PROZAC Weekly clinical trials — Treatment-emergent adverse reactions in clinical trials with PROZAC W eekly were similar to the adverse reactions reported by patients in clinical trials with PROZAC daily. In a placebo-controlled clinical trial, more patients taking PROZAC Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking PROZAC 20 mg daily (10% versus 5%, respectively). Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. 6.2 Other Reactions Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction. Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia, hypotension1 . Digestive System — Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage. Hemic and Lymphatic System — Infrequent: ecchymosis; Rare: petechia, purpura. Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder1, bruxism1 , buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions. Respiratory System — Rare: larynx edema. Skin and Appendages — Infrequent: alopecia; Rare: purpuric rash. Special Senses — Frequent: taste perversion; Infrequent: mydriasis. Urogenital System — Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding2 . 1 MedDRA dictionary term from integrated database of placebo controlled trials of 15870 patients, of which 9673 patients received fluoxetine. 2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of PROZAC. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with PROZAC that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including Torsades de Pointes–type arrhythmias), vaginal bleeding, and violent behaviors1 . 1 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. 7 DRUG INTERACTIONS As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. 7.1 Monoamine Oxidase Inhibitors (MAOI) [See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)]. 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of PROZAC and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)]. 7.3 Serotonergic Drugs [See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)]. 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7)]. 7.5 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. 7.6 Potential for Other Drugs to affect PROZAC Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs [see Clinical Pharmacology (12.3)]. 7.7 Potential for PROZAC to affect Other Drugs Pimozide — Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and PROZAC [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.8)]. Thioridazine — Thioridazine should not be administered with PROZAC or within a minimum of 5 weeks after PROZAC has been discontinued, because of the risk of QT Prolongation [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.8)]. In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine. Thioridazine administration produces a dose-related prolongation of the QT interval, which is associated with serious ventricular arrhythmias, such as Torsades de Pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Drugs Metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4.2)]. Tricyclic Antidepressants (TCAs) — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly [see Warnings and Precautions (5.2)]. Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect [see Clinical Pharmacology (12.3)]. Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Olanzapine — Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using PROZAC and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax. 7.8 Drugs that Prolong the QT Interval Do not use PROZAC in combination with thioridazine or pimozide. Use PROZAC with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). PROZAC is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of PROZAC. Concomitant use of other highly protein-bound drugs can increase the concentration of PROZAC [see Contraindications (4.2), Warnings and Precautions (5.11), Drug Interactions (7.7), and Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS When using PROZAC and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. 8.1 Pregnancy Pregnancy Category C — PROZAC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. Treatment of Pregnant Women during the First Trimester — There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. Nonteratogenic Effects — Neonates exposed to PROZAC and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 - 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including PROZAC) in pregnancy and PPHN. Other studies do not show a significant statistical association. Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with PROZAC, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis [see Dosage and Administration (2.7)]. Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m 2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). 8.2 Labor and Delivery The effect of PROZAC on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Because PROZAC is excreted in human milk, nursing while on PROZAC is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on PROZAC developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. 8.4 Pediatric Use Use of PROZAC in children — The efficacy of PROZAC for the treatment of Major Depressive Disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 [see Clinical Studies (14.1)]. The efficacy of PROZAC for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 [see Clinical Studies (14.2)]. The safety and effectiveness in pediatric patients <8 years of age in Major Depressive Disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with Major Depressive Disorder or OCD [see Clinical Pharmacology (12.3)]. The acute adverse reaction profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19-week Major Depressive Disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see Adverse Reactions (6.1)]. Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. [see Warnings and Precautions (5.6)]. PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Anyone considering the use of PROZAC in a child or adolescent must balance the potential risks with the clinical need. Animal Data — Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5-10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1-2 times the average AUC in pediatric patients at the MRHD of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1-0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 major metabolite, norfluoxetine, are approximately 0.3-0.8, 1-8, and 3-20 times, respectively, the pediatric exposure at the MRHD. A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. Use of PROZAC in combination with olanzapine in children and adolescents: Safety and efficacy of PROZAC and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with Bipolar I Disorder. Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 10 years of age have not been established. 8.5 Geriatric Use US fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.4)]. No overall differences in safety or 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. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.9)]. Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using PROZAC in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.7) and Clinical Pharmacology (12.4)]. 9 DRUG ABUSE AND DEPENDENCE 9.3 Dependence PROZAC has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with PROZAC did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of PROZAC (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). 10 OVERDOSAGE 10.1 Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as nodal rhythm, QT interval prolongation and ventricular arrhythmias, including Torsades de Pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 10.2 Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see Overdosage (10.3)]. 10.3 Management of Overdose For current information on the management of PROZAC overdose, contact a certified poison control center (1-800 222-1222 or www.poison.org). Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multi-drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use general supportive and symptomatic measures. Induction of emesis is not recommended. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Drug Interactions (7.7)]. For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert. 11 DESCRIPTION PROZAC® (fluoxetine capsules, USP) is a selective serotonin reuptake inhibitor for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17 H18 F3NO•HCl. Its molecular weight is 345.79. The structural formula is: structural formula Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol), 20 mg (64.7 µmol), or 40 mg (129.3 µmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10 and 20 mg Pulvules also contain FD&C Blue No. 1, and the 40 mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. PROZAC Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 µmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Although the exact mechanism of PROZAC is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. 12.2 Pharmacodynamics Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. 12.3 Pharmacokinetics Systemic Bioavailability — In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The Pulvule and PROZAC Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. PROZAC Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. Protein Binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important. Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions (7.7)]. Accumulation and Slow Elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used [see Warnings and Precautions (5.14)]. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of PROZAC. Weekly Dosing — Administration of PROZAC Weekly once weekly results in increased fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of clinical response. Peak concentrations from once-weekly doses of PROZAC Weekly capsules of fluoxetine are in the range of the average concentration for 20 mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20 mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly dosing are in relative proportion to the total dose administered. Average steady-state fluoxetine concentrations are approximately 50% lower following the once-weekly regimen compared with the once-daily regimen. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Cmax for fluoxetine following the 90 mg dose was approximately 1.7-fold higher than the C max value for the established 20 mg once-daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90 mg once-weekly dose and the last 20 mg once-daily dose were separated by 1 week, C max values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better to separate the first 90 mg weekly dose and the last 20 mg once-daily dose by 1 week [see Dosage and Administration (2.1)]. 12.4 Specific Populations Liver Disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used [see Dosage and Administration (2.7), Use in Specific Populations (8.6)]. Renal Disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. Geriatric Pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients. Pediatric Pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with Major Depressive Disorder or Obsessive Compulsive Disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with Major Depressive Disorder. Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m 2 basis], produced no evidence of carcinogenicity. Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of Fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)]. 13.2 Animal Toxicology and/or Pharmacology Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. 14 CLINICAL STUDIES Efficacy for PROZAC was established for the: Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 • Acute and maintenance treatment of Major Depressive Disorder in adults, and children and adolescents (8 to 18 years) in 7 short-term and 2 long-term, placebo-controlled trials [see Clinical Studies 14.1]. • Acute treatment of obsessions and compulsions in adults, and children and adolescents (7 to 17 years) with Obsessive Compulsive Disorder (OCD) in 3 short-term placebo-controlled trials [see Clinical Studies (14.2)]. • Acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa in 3 short-term and 1 long-term, placebo-controlled trials [see Clinical Studies (14.3)]. • Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients in 2 short-term, placebo- controlled trials [see Clinical Studies (14.4)]. Efficacy for PROZAC and olanzapine in combination was established for the: • Acute treatment of depressive episodes in Bipolar I Disorder in adults, and children and adolescents (10 to 17 years) in 3 short-term, placebo-controlled trials. • Acute and maintenance treatment of treatment resistant depression in adults (18 to 85 years) in 3 short-term, placebo-controlled trials and 1 randomized withdrawal study with an active control. When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. 14.1 Major Depressive Disorder Daily Dosing Adult — The efficacy of PROZAC was studied in 5- and 6-week placebo-controlled trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of Major Depressive Disorder. PROZAC was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). PROZAC was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. Two 6-week controlled studies (N=671, randomized) comparing PROZAC 20 mg and placebo have shown PROZAC 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with Major Depressive Disorder. In these studies, PROZAC produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. PROZAC was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between PROZAC (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on PROZAC 20 mg/day. These patients (N=298) were randomized to continuation on double-blind PROZAC 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking PROZAC compared with those on placebo. Pediatric (children and adolescents) — The efficacy of PROZAC 20 mg/day in children and adolescents (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) was studied in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of Major Depressive Disorder. In both studies independently, PROZAC produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Weekly dosing for Maintenance/Continuation Treatment A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for Major Depressive Disorder who had responded (defined as having a modified HAMD-17 score of ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for Major Depressive Disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with PROZAC 20 mg once daily. These patients were randomized to double-blind, once-weekly continuation treatment with PROZAC Weekly, PROZAC 20 mg once daily, or placebo. PROZAC Weekly once weekly and PROZAC 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of depressive symptoms) compared with placebo for a period of 25 weeks. However, the equivalence of these 2 treatments during continuation therapy has not been established. 14.2 Obsessive Compulsive Disorder Adult — The effectiveness of PROZAC for the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed PROZAC doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving PROZAC experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving PROZAC experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: Table 6 Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies PROZAC Outcome Classification Placebo 20 mg 40 mg 60 mg W orse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD (DSM-IV), patients received PROZAC 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. PROZAC produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. 14.3 Bulimia Nervosa The effectiveness of PROZAC for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of PROZAC or placebo in the morning. Patients in the 16-week study received a fixed PROZAC dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, PROZAC 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The PROZAC-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between PROZAC 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with PROZAC 60 mg/day, were randomized to continuation of PROZAC 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued PROZAC 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. 14.4 Panic Disorder The effectiveness of PROZAC in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia. Study 1 (N=180 randomized) was a 12-week flexible-dose study. PROZAC was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of PROZAC-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N=214 randomized) was a 12-week flexible-dose study. PROZAC was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of PROZAC-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively. 16 HOW SUPPLIED/STORAGE AND HANDLING Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________ 25 16.1 How Supplied The following products are manufactured by Eli Lilly and Company for Dista Products Company: Pulvule are available in 10mg, 20mg and 40mg capsule strengths and packages as follows: Pulvule Strength 10 mg1 20 mg1 40 mg1 Pulvule No.2 PU3104 PU3105 PU3107 Cap Color Opaque green Opaque green Opaque green Body Color Opaque green Opaque yellow Opaque orange Identification DISTA 3104 Prozac 10 mg DISTA 3105 Prozac 20 mg DISTA 3107 Prozac 40 mg NDC Codes: Bottles of 30 0777-3105-30 0777-3107-30 Bottles 100 0777-3104-02 0777-3105-02 Bottles of 2000 0777-3105-07 The following product is manufactured and distributed by Eli Lilly and Company: PROZAC® Weekly™ Capsules are available in: The 90 mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) – Blister package of 4 1 Fluoxetine base equivalent. 2 Protect from light. 16.2 Storage and Handling Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). 17 PATIENT COUNSELING INFORMATION See the FDA-approved Medication Guide. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking PROZAC as monotherapy or in combination with olanzapine. When using PROZAC and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax. 17.1 General Information Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with PROZAC and to reread it each time the prescription is renewed. Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with PROZAC and should counsel them in its appropriate use. Healthcare providers 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. Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking PROZAC. When using PROZAC and olanzapine in combination, also refer to the Medication Guide for Symbyax. 17.2 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults 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 [see Box Warning and Warnings and Precautions (5.1)]. 17.3 Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of PROZAC and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort [see Contraindications (4.1), Warnings and Precautions (5.2), and Drug Interactions (7.3)]. Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 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 cautioned to seek medical care immediately if they experience these symptoms. 17.4 Allergic Reactions and Rash Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions (5.3)]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms. 17.5 Abnormal Bleeding Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see Warnings and Precautions (5.7) and Drug Interactions (7.4)]. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking PROZAC. 17.6 Angle-Closure Glaucoma Patients should be advised that taking Prozac 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. [See Warnings and Precautions (5.8)] 17.7 Hyponatremia Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including PROZAC. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions (5.9)]. 17.8 QT Prolongation Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with PROZAC. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia [see Warnings and Precautions (5.11)]. 17.9 Potential for Cognitive and Motor Impairment PROZAC may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions (5.13)]. 17.10 Use of Concomitant Medications Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax, Sarafem, or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on PROZAC. 17.11 Discontinuation of Treatment Patients should be advised to take PROZAC exactly as prescribed, and to continue taking PROZAC as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking PROZAC without consulting their physician [see Warnings and Precautions (5.15)]. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with PROZAC. 17.12 Use in Specific Populations Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. Nursing Mothers — Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy. Because PROZAC is excreted in human milk, nursing while taking PROZAC is not recommended [see Use in Specific Populations (8.3)]. Pediatric Use of PROZAC — PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine. [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)]. Pediatric Use of PROZAC and olanzapine in combination - Safety and efficacy of PROZAC and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions (5.16) and Use in Specific Populations (8.4)]. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 Literature revised Month dd, yyyy Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 1987, yyyy, Eli Lilly and Company. All rights reserved. PRZ-A3.0-0001-USPI Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Medication Guide PROZAC® (PRO-zac) (fluoxetine hydrochloride) Pulvule® and Weekly™ Capsule Read the Medication Guide that comes with PROZAC before you start 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 healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about PROZAC? PROZAC and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: • PROZAC and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. • Watch for these changes and call your healthcare provider right away if you notice: • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. • Pay particular attention to such changes when PROZAC is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: • attempts to commit suicide • acting on dangerous impulses • acting aggressive or violent • thoughts about suicide or dying • new or worse depression • new or worse anxiety or panic attacks • feeling agitated, restless, angry or irritable • trouble sleeping Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 • an increase in activity or talking more than what is normal for you • other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. PROZAC may be associated with these serious side effects: 2. Serotonin Syndrome. This condition can be life-threatening and may include: • agitation, hallucinations, coma or other changes in mental status • coordination problems or muscle twitching (overactive reflexes) • racing heartbeat, high or low blood pressure • sweating or fever • nausea, vomiting, or diarrhea • muscle rigidity • dizziness • flushing • tremor • seizures 3. Severe allergic reactions: • trouble breathing • swelling of the face, tongue, eyes or mouth • rash, itchy welts (hives) or blisters, alone or with fever or joint pain 4. Abnormal bleeding: PROZAC and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 5. 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. 6. Seizures or convulsions 7. Manic episodes: • greatly increased energy • severe trouble sleeping • racing thoughts Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 • reckless behavior • unusually grand ideas • excessive happiness or irritability • talking more or faster than usual 8. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment. 9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include: • headache • weakness or feeling unsteady • confusion, problems concentrating or thinking or memory problems 10. Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsades de Pointes). This condition can be life threatening. The symptoms may include: • fast, slow, or irregular heartbeat • shortness of breath • dizziness or fainting Do not stop PROZAC without first talking to your healthcare provider. Stopping PROZAC too quickly may cause serious symptoms including: • anxiety, irritability, high or low mood, feeling restless or changes in sleep habits • headache, sweating, nausea, dizziness • electric shock-like sensations, shaking, confusion What is PROZAC? PROZAC is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. PROZAC is used to treat: • Major Depressive Disorder (MDD) • Obsessive Compulsive Disorder (OCD) • Bulimia Nervosa • Panic Disorder* • Depressive episodes associated with Bipolar I Disorder, taken with olanzapine (Zyprexa) • Treatment Resistant Depression (depression that has not gotten better with at least 2 other treatments), taken with olanzapine (Zyprexa)* *Not approved for use in children Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Talk to your healthcare provider if you do not think that your condition is getting better with PROZAC treatment. Who should not take PROZAC? Do not take PROZAC if you: • are allergic to fluoxetine hydrochloride or any of the ingredients in PROZAC. See the end of this Medication Guide for a complete list of ingredients in PROZAC. • 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 5 weeks of stopping PROZAC unless directed to do so by your physician. • Do not start PROZAC if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take PROZAC close in time to an MAOI may have serious or even life- threatening side effects. Get medical help right away if you have any of these symptoms: • high fever • uncontrolled muscle spasms • stiff muscles • rapid changes in heart rate or blood pressure • confusion • loss of consciousness (pass out) • take Mellaril® (thioridazine). Do not take Mellaril® within 5 weeks of stopping PROZAC because this can cause serious heart rhythm problems or sudden death. • take the antipsychotic medicine pimozide (Orap®) because this can cause serious heart problems. What should I tell my healthcare provider before taking PROZAC? Ask if you are not sure. Before starting PROZAC, tell your healthcare provider if you: • Are taking certain drugs or treatments such as: • Triptans used to treat migraine headache • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs, MAOIs or antipsychotics • Tramadol and fentanyl • Over-the-counter supplements such as tryptophan or St. John’s Wort • Electroconvulsive therapy (ECT) Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 • have liver problems • have kidney problems • have heart problems • have or had seizures or convulsions • have bipolar disorder or mania • have low sodium levels in your blood • have a history of a stroke • have high blood pressure • have or had bleeding problems • are pregnant or plan to become pregnant. It is not known if PROZAC will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy. • are breast-feeding or plan to breast-feed. Some PROZAC may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking PROZAC. Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. PROZAC and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take PROZAC with your other medicines. Do not start or stop any medicine while taking PROZAC without talking to your healthcare provider first. If you take PROZAC, you should not take any other medicines that contain fluoxetine hydrochloride including: • Symbyax • Sarafem • Prozac Weekly How should I take PROZAC? • Take PROZAC exactly as prescribed. Your healthcare provider may need to change the dose of PROZAC until it is the right dose for you. • PROZAC may be taken with or without food. • If you miss a dose of PROZAC, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of PROZAC at the same time. • If you take too much PROZAC, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking PROZAC? PROZAC can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 dangerous activities until you know how PROZAC affects you. Do not drink alcohol while using PROZAC. What are the possible side effects of PROZAC? PROZAC may cause serious side effects, including: • See “What is the most important information I should know about PROZAC?” • Problems with blood sugar control. People who have diabetes and take PROZAC may have problems with low blood sugar while taking PROZAC. High blood sugar can happen when PROZAC is stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking PROZAC. • Feeling anxious or trouble sleeping Common possible side effects in people who take PROZAC include: • unusual dreams • sexual problems • loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth • flu symptoms • feeling tired or fatigued • change in sleep habits • yawning • sinus infection or sore throat • tremor or shaking • sweating • feeling anxious or nervous • hot flashes • rash Other side effects in children and adolescents include: • increased thirst • abnormal increase in muscle movement or agitation • nose bleed • urinating more often • heavy menstrual periods • possible slowed growth rate and weight change. Your child’s height and weight should be monitored during treatment with PROZAC. 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 PROZAC. For more information, ask your healthcare provider or pharmacist. Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store PROZAC? • Store PROZAC at room temperature between 59°F and 86°F (15°C to 30°C). • Keep PROZAC away from light. • Keep PROZAC bottle closed tightly. Keep PROZAC and all medicines out of the reach of children. General information about PROZAC Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PROZAC for a condition for which it was not prescribed. Do not give PROZAC to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about PROZAC. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about PROZAC that is written for healthcare professionals. For more information about PROZAC call 1-800-Lilly-Rx (1-800-545-5979). What are the ingredients in PROZAC? Active ingredient: fluoxetine hydrochloride Inactive ingredients: • PROZAC pulvules: starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10 and 20 mg Pulvules also contain FD&C Blue No. 1, and the 40 mg Pulvules also contains FD&C Blue No. 1 and FD&C Yellow No. 6. • PROZAC Weekly™ capsules: D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium oxide, triethyl citrate, and other inactive ingredients. This Medication Guide has been approved by the U.S. Food and Drug Administration. Medication Guide revised Month dd, yyyy Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 2009, yyyy, Eli Lilly and Company. All rights reserved. PRZ-C2.0-0000-MG Reference ID: 3642387 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:07.720339	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018936s102lbl.pdf', 'application_number': 18936, 'submission_type': 'SUPPL ', 'submission_number': 102}
11,387	NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 3 EC-NAPROSYN® (naproxen delayed-release tablets) NAPROSYN® (naproxen tablets) ANAPROX®/ANAPROX® DS (naproxen sodium tablets) NAPROSYN® (naproxen suspension) Rx only Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). • Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). DESCRIPTION Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2- naphthaleneacetic acid and (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen sodium have the following structures, respectively: Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of C14H13NaO3. Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 4 NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of naproxen, peach tablets containing 375 mg of naproxen and yellow tablets containing 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, iron oxides, povidone and magnesium stearate. EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-coated white tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified water. The dispersion may also contain simethicone emulsion. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH 4. ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue tablets containing 550 mg of naproxen sodium for oral administration. The inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Opadry YS-1- 4216. NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle containing sucrose, magnesium aluminum silicate, sorbitol solution and sodium chloride (30 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified water. The pH of the suspension ranges from 2.2 to 3.7. CLINICAL PHARMACOLOGY Pharmacodynamics Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Naproxen itself is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 5 Absorption Immediate Release After administration of NAPROSYN tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours. Delayed Release EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC- NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC- NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there were no differences in total absorption as measured by Cmax and AUC: EC-NAPROSYN* 500 mg bid NAPROSYN* 500 mg bid Cmax (µg/mL) 94.9 (18%) 97.4 (13%) Tmax (hours) 4 (39%) 1.9 (61%) AUC0–12 hr (µg·hr/mL) 845 (20%) 767 (15%) Mean value (coefficient of variation) Antacid Effects When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly. Food Effects When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax). Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 6 concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS, Nursing Mothers). Metabolism Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. In patients with renal failure metabolites may accumulate (see WARNINGS, Renal Effects). Special Populations Pediatric Patients In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND ADMINISTRATION) were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN has not been studied in subjects under the age of 18. Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is < 1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Race Pharmacokinetic differences due to race have not been studied. Hepatic Insufficiency Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Renal Insufficiency Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 7 recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS, Renal Effects). CLINICAL STUDIES General Information Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (eg, decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 8 naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These studies indicated that EC-NAPROSYN and NAPROSYN showed no significant differences in efficacy or safety and had similar prevalence of minor GI complaints. Individual patients, however, may find one formulation preferable to the other. Five hundred and fifty-three patients received EC-NAPROSYN during long-term open-label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use. Geriatric Patients The hepatic and renal tolerability of long-term naproxen administration was studied in two double- blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is indicated: • For the relief of the signs and symptoms of rheumatoid arthritis • For the relief of the signs and symptoms of osteoarthritis • For the relief of the signs and symptoms of ankylosing spondylitis • For the relief of the signs and symptoms of juvenile arthritis Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the patient’s weight. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 9 Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is also indicated: • For relief of the signs and symptoms of tendonitis • For relief of the signs and symptoms of bursitis • For relief of the signs and symptoms of acute gout • For the management of pain • For the management of primary dysmenorrhea EC-NAPROSYN is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated in patients with known hypersensitivity to naproxen and naproxen sodium. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions and PRECAUTIONS, Preexisting Asthma). NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDS, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see GI WARNINGS). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 10 Hypertension NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used with caution in patients with fluid retention, hypertension, or heart failure. Since each ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of naproxen) of sodium, this should be considered in patients whose overall intake of sodium must be severely restricted. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 11 Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state (see WARNINGS, Advanced Renal Disease). Advanced Renal Disease No information is available from controlled clinical studies regarding the use of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension in patients with advanced renal disease. Therefore, treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is not recommended in these patients with advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 12 PRECAUTIONS General Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically. The pharmacological activity of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension should be discontinued. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use 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 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 13 Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin- sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation). 3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 14 observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (eg, difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. 8. Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be discontinued. Drug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE- inhibitors. Aspirin When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is administered with aspirin, its protein binding is reduced, although the clearance of free NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of naproxen and naproxen sodium and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as postmarketing observations, have shown that NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 15 Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. No significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants. However, caution is advised since interactions have been seen with other nonsteroidal agents of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function. Other Information Concerning Drug Interactions Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of EC-NAPROSYN is not recommended. Drug/Laboratory Test Interaction Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 16 Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). The maximum dose used was 0.28 times the systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found. Pregnancy Teratogenic Effects Pregnancy Category C Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti- inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension on labor and delivery in pregnant women are unknown. Nursing Mothers The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 17 Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND ADMINISTRATION), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. Geriatric Use Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. While age does not appear to be an independent risk factor for the development of peptic ulceration and bleeding with naproxen administration, eElderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS). Naproxen 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. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs (see WARNINGS, Renal Effects). ADVERSE REACTIONS Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen (see CLINICAL PHARMACOLOGY). In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 18 Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: edema, palpitations General: dyspnea, thirst *Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice, pancreatitis, vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal ulceration, ulcerative stomatitis Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction Respiratory: eosinophilic pneumonitis Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 19 In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, hepatitis, eructation, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria OVERDOSAGE Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs. Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding. DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 20 After observing the response to initial therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient's needs. Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation. Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the stomach, the absorption of the drug is delayed compared to the other naproxen formulations (see CLINICAL PHARMACOLOGY). The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS). Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Patients With Moderate to Severe Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Effects). Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis NAPROSYN 250 mg or 375 mg or 500 mg twice daily twice daily twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp) or 375 mg (15 mL/3 tsp) or 500 mg (20 mL/4 tsp) twice daily twice daily twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 21 morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY). Juvenile Arthritis The use of NAPROSYN Suspension allows for more flexible dose titration. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen (see CLINICAL PHARMACOLOGY). The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing of NAPROSYN Suspension: Patient’s Weight Dose Administered as 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN may also be used but EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). Acute Gout The recommended starting dose is 750 mg of NAPROSYN followed by 250 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). HOW SUPPLIED NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on one side and scored on the other. Packaged in light-resistant bottles of 100. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 22 100’s (bottle): NDC 0004-6313-01. 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6314-01. 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6316-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant containers. NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28). Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). Dispense in light- resistant containers. EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, capsule-shaped, imprinted with EC- NAPROSYN on one side and 375 on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6415-01. 500 mg: white, capsule-shaped, imprinted with EC-NAPROSYN on one side and 500 on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6416-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant containers. ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with NPS-275 on one side. Packaged in bottles of 100. 100’s (bottle): NDC 0004-6202-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers. ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong-shaped, engraved with NPS 550 on one side and scored on both sides. Packaged in bottles of 100. 100’s (bottle): NDC 0004-6203-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers. ALEVE is a registered trademark of Bayer Healthcare LLC. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 23 Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non- Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).” NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: • can happen without warning symptoms • may cause death The chance of a person getting an ulcer or bleeding increases with: • taking medicines called “corticosteroids” and “anticoagulants” • longer use • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as: • different types of arthritis • menstrual cramps and other types of short-term pain This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 24 Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider: • about all your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness Get emergency help right away if you have any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 25 Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 Flurbirofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 This Medication Guide has been approved by the U.S. Food and Drug Administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:07.764955	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017581s106,018164s056,018965s014,020067s011lbl.pdf', 'application_number': 18965, 'submission_type': 'SUPPL ', 'submission_number': 14}
11,386	1 1 EC-NAPROSYN® (naproxen delayed-release tablets) 2 NAPROSYN® (naproxen tablets) 3 ANAPROX®/ANAPROX® DS (naproxen sodium tablets) 4 NAPROSYN® (naproxen suspension) 5 Rx only 6 Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). • Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). DESCRIPTION 7 Naproxen is a proprionic acid derivative related to the arylacetic acid group of 8 nonsteroidal anti-inflammatory drugs. 9 The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α- 10 methyl-2-naphthaleneacetic acid and (S)-6-methoxy-α-methyl-2- 11 naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen 12 sodium have the following structures, respectively: 13 14 Naproxen has a molecular weight of 230.26 and a molecular formula of 15 C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a 16 molecular formula of C14H13NaO3. 17 Naproxen is an odorless, white to off-white crystalline substance. It is lipid- 18 soluble, practically insoluble in water at low pH and freely soluble in water at 19 high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 2 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely 21 soluble in water at neutral pH. 22 NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 23 mg of naproxen, pink tablets containing 375 mg of naproxen and yellow 24 tablets containing 500 mg of naproxen for oral administration. The inactive 25 ingredients are croscarmellose sodium, iron oxides, povidone and magnesium 26 stearate. 27 EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric- 28 coated white tablets containing 375 mg of naproxen and 500 mg of naproxen 29 for oral administration. The inactive ingredients are croscarmellose sodium, 30 povidone and magnesium stearate. The enteric coating dispersion contains 31 methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and 32 purified water. The dispersion may also contain simethicone emulsion. The 33 dissolution of this enteric-coated naproxen tablet is pH dependent with rapid 34 dissolution above pH 6. There is no dissolution below pH 4. 35 ANAPROX (naproxen sodium tablets) is available as blue tablets containing 36 275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is 37 available as dark blue tablets containing 550 mg of naproxen sodium for oral 38 administration. The inactive ingredients are magnesium stearate, 39 microcrystalline cellulose, povidone and talc. The coating suspension for the 40 ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910, 41 Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The 42 coating suspension for the ANAPROX DS 550 mg tablet may contain 43 hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene 44 glycol 8000 or Opadry YS-1-4216. 45 NAPROSYN (naproxen suspension) is available as a light orange-colored 46 opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle 47 containing sucrose, magnesium aluminum silicate, sorbitol solution and 48 sodium chloride (30 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C 49 Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified 50 water. The pH of the suspension ranges from 2.2 to 3.7. 51 CLINICAL PHARMACOLOGY 52 Pharmacodynamics 53 Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic 54 and antipyretic properties. The sodium salt of naproxen has been developed as 55 a more rapidly absorbed formulation of naproxen for use as an analgesic. The 56 mechanism of action of the naproxen anion, like that of other NSAIDs, is not 57 completely understood but may be related to prostaglandin synthetase 58 inhibition. 59 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 3 Pharmacokinetics 60 Naproxen and naproxen sodium are rapidly and completely absorbed from the 61 gastrointestinal tract with an in vivo bioavailability of 95%. The different 62 dosage forms of NAPROSYN are bioequivalent in terms of extent of 63 absorption (AUC) and peak concentration (Cmax); however, the products do 64 differ in their pattern of absorption. These differences between naproxen 65 products are related to both the chemical form of naproxen used and its 66 formulation. Even with the observed differences in pattern of absorption, the 67 elimination half-life of naproxen is unchanged across products ranging from 68 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and 69 the degree of naproxen accumulation is consistent with this half-life. This 70 suggests that the differences in pattern of release play only a negligible role in 71 the attainment of steady-state plasma levels. 72 Absorption 73 Immediate Release 74 After administration of NAPROSYN tablets, peak plasma levels are attained 75 in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels 76 are attained in 1 to 2 hours. The difference in rates between the two products 77 is due to the increased aqueous solubility of the sodium salt of naproxen used 78 in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN 79 Suspension are attained in 1 to 4 hours. 80 Delayed Release 81 EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier 82 to disintegration in the acidic environment of the stomach and to lose integrity 83 in the more neutral environment of the small intestine. The enteric polymer 84 coating selected for EC-NAPROSYN dissolves above pH 6. When EC- 85 NAPROSYN was given to fasted subjects, peak plasma levels were attained 86 about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo 87 study in man using radiolabeled EC-NAPROSYN tablets demonstrated that 88 EC-NAPROSYN dissolves primarily in the small intestine rather than in the 89 stomach, so the absorption of the drug is delayed until the stomach is emptied. 90 When EC-NAPROSYN and NAPROSYN were given to fasted subjects 91 (n=24) in a crossover study following 1 week of dosing, differences in time to 92 peak plasma levels (Tmax) were observed, but there were no differences in total 93 absorption as measured by Cmax and AUC: 94 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 4 EC-NAPROSYN* 500 mg bid NAPROSYN* 500 mg bid Cmax (µg/mL) 94.9 (18%) 97.4 (13%) Tmax (hours) 4 (39%) 1.9 (61%) AUC0–12 hr (µg·hr/mL) 845 (20%) 767 (15%) Mean value (coefficient of variation) 95 Antacid Effects 96 When EC-NAPROSYN was given as a single dose with antacid (54 mEq 97 buffering capacity), the peak plasma levels of naproxen were unchanged, but 98 the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with 99 antacid 5 hours), although not significantly. 100 Food Effects 101 When EC-NAPROSYN was given as a single dose with food, peak plasma 102 levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). 103 Residence time in the small intestine until disintegration was independent of 104 food intake. The presence of food prolonged the time the tablets remained in 105 the stomach, time to first detectable serum naproxen levels, and time to 106 maximal naproxen levels (Tmax), but did not affect peak naproxen levels 107 (Cmax). 108 Distribution 109 Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels 110 naproxen is greater than 99% albumin-bound. At doses of naproxen greater 111 than 500 mg/day there is less than proportional increase in plasma levels due 112 to an increase in clearance caused by saturation of plasma protein binding at 113 higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 114 1500 mg daily doses of naproxen, respectively). The naproxen anion has been 115 found in the milk of lactating women at a concentration equivalent to 116 approximately 1% of maximum naproxen concentration in plasma (see 117 PRECAUTIONS: Nursing Mothers). 118 Metabolism 119 Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, 120 and both parent and metabolites do not induce metabolizing enzymes. Both 121 naproxen and 6-0-desmethyl naproxen are further metabolized to their 122 respective acylglucuronide conjugated metabolites. 123 Excretion 124 The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the 125 naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 126 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma 127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 5 half-life of the naproxen anion in humans ranges from 12 to 17 hours. The 128 corresponding half-lives of both naproxen’s metabolites and conjugates are 129 shorter than 12 hours, and their rates of excretion have been found to coincide 130 closely with the rate of naproxen disappearance from the plasma. Small 131 amounts, 3% or less of the administered dose, are excreted in the feces. In 132 patients with renal failure metabolites may accumulate (see WARNINGS: 133 Renal Effects). 134 Special Populations 135 Pediatric Patients 136 In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels 137 following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND 138 ADMINISTRATION) were found to be similar to those found in normal 139 adults following a 500 mg dose. The terminal half-life appears to be similar in 140 pediatric and adult patients. Pharmacokinetic studies of naproxen were not 141 performed in pediatric patients younger than 5 years of age. Pharmacokinetic 142 parameters appear to be similar following administration of naproxen 143 suspension or tablets in pediatric patients. EC-NAPROSYN has not been 144 studied in subjects under the age of 18. 145 Geriatric Patients 146 Studies indicate that although total plasma concentration of naproxen is 147 unchanged, the unbound plasma fraction of naproxen is increased in the 148 elderly, although the unbound fraction is < 1% of the total naproxen 149 concentration. Unbound trough naproxen concentrations in elderly subjects 150 have been reported to range from 0.12% to 0.19% of total naproxen 151 concentration, compared with 0.05% to 0.075% in younger subjects. The 152 clinical significance of this finding is unclear, although it is possible that the 153 increase in free naproxen concentration could be associated with an increase 154 in the rate of adverse events per a given dosage in some elderly patients. 155 Race 156 Pharmacokinetic differences due to race have not been studied. 157 Hepatic Insufficiency 158 Naproxen pharmacokinetics has not been determined in subjects with hepatic 159 insufficiency. 160 Renal Insufficiency 161 Naproxen pharmacokinetics has not been determined in subjects with renal 162 insufficiency. Given that naproxen, its metabolites and conjugates are 163 primarily excreted by the kidney, the potential exists for naproxen metabolites 164 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 6 to accumulate in the presence of renal insufficiency. Elimination of naproxen 165 is decreased in patients with severe renal impairment. Naproxen-containing 166 products are not recommended for use in patients with moderate to severe and 167 severe renal impairment (creatinine clearance <30 mL/min) (see 168 WARNINGS: Renal Effects). 169 CLINICAL STUDIES 170 General Information 171 Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, 172 juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute 173 gout. Improvement in patients treated for rheumatoid arthritis was 174 demonstrated by a reduction in joint swelling, a reduction in duration of 175 morning stiffness, a reduction in disease activity as assessed by both the 176 investigator and patient, and by increased mobility as demonstrated by a 177 reduction in walking time. Generally, response to naproxen has not been 178 found to be dependent on age, sex, severity or duration of rheumatoid arthritis. 179 In patients with osteoarthritis, the therapeutic action of naproxen has been 180 shown by a reduction in joint pain or tenderness, an increase in range of 181 motion in knee joints, increased mobility as demonstrated by a reduction in 182 walking time, and improvement in capacity to perform activities of daily 183 living impaired by the disease. 184 In a clinical trial comparing standard formulations of naproxen 375 mg bid 185 (750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group 186 terminated prematurely because of adverse events. Nineteen patients in the 187 1500 mg group terminated prematurely because of adverse events. Most of 188 these adverse events were gastrointestinal events. 189 In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and 190 juvenile arthritis, naproxen has been shown to be comparable to aspirin and 191 indomethacin in controlling the aforementioned measures of disease activity, 192 but the frequency and severity of the milder gastrointestinal adverse effects 193 (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, 194 dizziness, lightheadedness) were less in naproxen-treated patients than in 195 those treated with aspirin or indomethacin. 196 In patients with ankylosing spondylitis, naproxen has been shown to decrease 197 night pain, morning stiffness and pain at rest. In double-blind studies the drug 198 was shown to be as effective as aspirin, but with fewer side effects. 199 In patients with acute gout, a favorable response to naproxen was shown by 200 significant clearing of inflammatory changes (eg, decrease in swelling, heat) 201 within 24 to 48 hours, as well as by relief of pain and tenderness. 202 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 7 Naproxen has been studied in patients with mild to moderate pain secondary 203 to postoperative, orthopedic, postpartum episiotomy and uterine contraction 204 pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in 205 patients taking naproxen and within 30 minutes in patients taking naproxen 206 sodium. Analgesic effect was shown by such measures as reduction of pain 207 intensity scores, increase in pain relief scores, decrease in numbers of patients 208 requiring additional analgesic medication, and delay in time to remedication. 209 The analgesic effect has been found to last for up to 12 hours. 210 Naproxen may be used safely in combination with gold salts and/or 211 corticosteroids; however, in controlled clinical trials, when added to the 212 regimen of patients receiving corticosteroids, it did not appear to cause greater 213 improvement over that seen with corticosteroids alone. Whether naproxen has 214 a “steroid-sparing” effect has not been adequately studied. When added to the 215 regimen of patients receiving gold salts, naproxen did result in greater 216 improvement. Its use in combination with salicylates is not recommended 217 because there is evidence that aspirin increases the rate of excretion of 218 naproxen and data are inadequate to demonstrate that naproxen and aspirin 219 produce greater improvement over that achieved with aspirin alone. In 220 addition, as with other NSAIDs, the combination may result in higher 221 frequency of adverse events than demonstrated for either product alone. 222 In 51Cr blood loss and gastroscopy studies with normal volunteers, daily 223 administration of 1000 mg of naproxen as 1000 mg of NAPROSYN 224 (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been 225 demonstrated to cause statistically significantly less gastric bleeding and 226 erosion than 3250 mg of aspirin. 227 Three 6-week, double-blind, multicenter studies with EC-NAPROSYN 228 (naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, 229 n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, 230 including 355 rheumatoid arthritis and osteoarthritis patients who had a recent 231 history of NSAID-related GI symptoms. These studies indicated that EC- 232 NAPROSYN and NAPROSYN showed no significant differences in efficacy 233 or safety and had similar prevalence of minor GI complaints. Individual 234 patients, however, may find one formulation preferable to the other. 235 Five hundred and fifty-three patients received EC-NAPROSYN during long- 236 term open-label trials (mean length of treatment was 159 days). The rates for 237 clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been 238 historically reported for long-term NSAID use. 239 Geriatric Patients 240 The hepatic and renal tolerability of long-term naproxen administration was 241 studied in two double-blind clinical trials involving 586 patients. Of the 242 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 8 patients studied, 98 patients were age 65 and older and 10 of the 98 patients 243 were age 75 and older. Naproxen was administered at doses of 375 mg twice 244 daily or 750 mg twice daily for up to 6 months. Transient abnormalities of 245 laboratory tests assessing hepatic and renal function were noted in some 246 patients, although there were no differences noted in the occurrence of 247 abnormal values among different age groups. 248 INDICATIONS AND USAGE 249 Carefully consider the potential benefits and risks of NAPROSYN, EC- 250 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and 251 other treatment options before deciding to use NAPROSYN, EC- 252 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use 253 the lowest effective dose for the shortest duration consistent with individual 254 patient treatment goals (see WARNINGS). 255 Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 256 NAPROSYN Suspension is indicated: 257 • For the relief of the signs and symptoms of rheumatoid arthritis 258 • For the relief of the signs and symptoms of osteoarthritis 259 • For the relief of the signs and symptoms of ankylosing spondylitis 260 • For the relief of the signs and symptoms of juvenile arthritis 261 Naproxen as NAPROSYN Suspension is recommended for juvenile 262 rheumatoid arthritis in order to obtain the maximum dosage flexibility based 263 on the patient’s weight. 264 Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN 265 Suspension is also indicated: 266 • For relief of the signs and symptoms of tendonitis 267 • For relief of the signs and symptoms of bursitis 268 • For relief of the signs and symptoms of acute gout 269 • For the management of pain 270 • For the management of primary dysmenorrhea 271 EC-NAPROSYN is not recommended for initial treatment of acute pain 272 because the absorption of naproxen is delayed compared to absorption from 273 other naproxen-containing products (see CLINICAL PHARMACOLOGY 274 and DOSAGE AND ADMINISTRATION). 275 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 9 CONTRAINDICATIONS 276 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 277 NAPROSYN Suspension are contraindicated in patients with known 278 hypersensitivity to naproxen and naproxen sodium. 279 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 280 NAPROSYN Suspension should not be given to patients who have 281 experienced asthma, urticaria, or allergic-type reactions after taking aspirin or 282 other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs 283 have been reported in such patients (see WARNINGS: Anaphylactoid 284 Reactions and PRECAUTIONS: Preexisting Asthma). 285 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 286 NAPROSYN Suspension are contraindicated for the treatment of peri- 287 operative pain in the setting of coronary artery bypass graft (CABG) surgery 288 (see WARNINGS). 289 WARNINGS 290 CARDIOVASCULAR EFFECTS 291 Cardiovascular Thrombotic Events 292 Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 293 three years duration have shown an increased risk of serious cardiovascular 294 (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. 295 All NSAIDS, both COX-2 selective and nonselective, may have a similar risk. 296 Patients with known CV disease or risk factors for CV disease may be at 297 greater risk. To minimize the potential risk for an adverse CV event in patients 298 treated with an NSAID, the lowest effective dose should be used for the 299 shortest duration possible. Physicians and patients should remain alert for the 300 development of such events, even in the absence of previous CV symptoms. 301 Patients should be informed about the signs and/or symptoms of serious CV 302 events and the steps to take if they occur. 303 There is no consistent evidence that concurrent use of aspirin mitigates the 304 increased risk of serious CV thrombotic events associated with NSAID use. 305 The concurrent use of aspirin and an NSAID does increase the risk of serious 306 GI events (see Gastrointestinal Effects – Risk of Ulceration, Bleeding, and 307 Perforation). 308 Two large, controlled, clinical trials of a COX-2 selective NSAID for the 309 treatment of pain in the first 10-14 days following CABG surgery found an 310 increased incidence of myocardial infarction and stroke (see 311 CONTRAINDICATIONS). 312 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 10 Hypertension 313 NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 314 ANAPROX DS and NAPROSYN Suspension, can lead to onset of new 315 hypertension or worsening of pre-existing hypertension, either of which may 316 contribute to the increased incidence of CV events. Patients taking thiazides or 317 loop diuretics may have impaired response to these therapies when taking 318 NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 319 ANAPROX DS and NAPROSYN Suspension, should be used with caution in 320 patients with hypertension. Blood pressure (BP) should be monitored closely 321 during the initiation of NSAID treatment and throughout the course of 322 therapy. 323 Congestive Heart Failure and Edema 324 Fluid retention, edema, and peripheral edema have been observed in some 325 patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX, 326 ANAPROX DS and NAPROSYN Suspension should be used with caution in 327 patients with fluid retention, hypertension, or heart failure. Since each 328 ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium 329 (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of 330 NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of 331 naproxen) of sodium, this should be considered in patients whose overall 332 intake of sodium must be severely restricted. 333 Gastrointestinal Effects – Risk of Ulceration, Bleeding, and 334 Perforation 335 NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 336 ANAPROX DS and NAPROSYN Suspension, can cause serious 337 gastrointestinal (GI) adverse events including inflammation, bleeding, 338 ulceration, and perforation of the stomach, small intestine, or large intestine, 339 which can be fatal. 340 These serious adverse events can occur at any time, with or without warning 341 symptoms, in patients treated with NSAIDs. Only one in five patients, who 342 develop a serious upper GI adverse event on NSAID therapy, is symptomatic. 343 Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in 344 approximately 1% of patients treated for 3-6 months, and in about 2-4% of 345 patients treated for one year. These trends continue with longer duration of 346 use, increasing the likelihood of developing a serious GI event at some time 347 during the course of therapy. However, even short-term therapy is not without 348 risk. The utility of periodic laboratory monitoring has not been demonstrated, 349 nor has it been adequately assessed. Only 1 in 5 patients who develop a 350 serious upper GI adverse event on NSAID therapy is symptomatic. 351 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 11 NSAIDs should be prescribed with extreme caution in those with a prior 352 history of ulcer disease or gastrointestinal bleeding. Patients with a prior 353 history of peptic ulcer disease and/or gastrointestinal bleeding who use 354 NSAIDs have a greater than 10-fold increased risk for developing a GI bleed 355 compared to patients with neither of these risk factors. Other factors that 356 increase the risk for GI bleeding in patients treated with NSAIDs include 357 concomitant use of oral corticosteroids or anticoagulants, longer duration of 358 NSAID therapy, smoking, use of alcohol, older age, and poor general health 359 status. Most spontaneous reports of fatal GI events are in elderly or debilitated 360 patients and therefore, special care should be taken in treating this population. 361 To minimize the potential risk for an adverse GI event in patients treated with 362 an NSAID, the lowest effective dose should be used for the shortest possible 363 duration. Patients and physicians should remain alert for signs and symptoms 364 of GI ulceration and bleeding during NSAID therapy and promptly initiate 365 additional evaluation and treatment if a serious GI adverse event is suspected. 366 This should include discontinuation of the NSAID until a serious GI adverse 367 event is ruled out. For high risk patients, alternate therapies that do not 368 involve NSAIDs should be considered. 369 Renal Effects 370 Long-term administration of NSAIDs has resulted in renal papillary necrosis 371 and other renal injury. Renal toxicity has also been seen in patients in whom 372 renal prostaglandins have a compensatory role in the maintenance of renal 373 perfusion. In these patients, administration of a nonsteroidal 374 anti-inflammatory drug may cause a dose-dependent reduction in 375 prostaglandin formation and, secondarily, in renal blood flow, which may 376 precipitate overt renal decompensation. Patients at greatest risk of this 377 reaction are those with impaired renal function, hypovolemia, heart failure, 378 liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, 379 and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug 380 therapy is usually followed by recovery to the pretreatment state (see 381 WARNINGS: Advanced Renal Disease). 382 Advanced Renal Disease 383 No information is available from controlled clinical studies regarding the use 384 of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 385 NAPROSYN Suspension in patients with advanced renal disease. Therefore, 386 treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS 387 and NAPROSYN Suspension is not recommended in these patients with 388 advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX, 389 ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close 390 monitoring of the patient’s renal function is advisable. 391 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 12 Anaphylactoid Reactions 392 As with other NSAIDs, anaphylactoid reactions may occur in patients without 393 known prior exposure to either NAPROSYN, EC-NAPROSYN, ANAPROX, 394 ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC- 395 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension 396 should not be given to patients with the aspirin triad. This symptom complex 397 typically occurs in asthmatic patients who experience rhinitis with or without 398 nasal polyps, or who exhibit severe, potentially fatal bronchospasm after 399 taking aspirin or other NSAIDs (see CONTRAINDICATIONS and 400 PRECAUTIONS: Preexisting Asthma). Emergency help should be sought 401 in cases where an anaphylactoid reaction occurs. 402 Skin Reactions 403 NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 404 ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse 405 events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and 406 toxic epidermal necrolysis (TEN), which can be fatal. These serious events 407 may occur without warning. Patients should be informed about the signs and 408 symptoms of serious skin manifestations and use of the drug should be 409 discontinued at the first appearance of skin rash or any other sign of 410 hypersensitivity. 411 Pregnancy 412 In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, 413 ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided 414 because it may cause premature closure of the ductus arteriosus. 415 PRECAUTIONS 416 General 417 Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, 418 ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, and 419 other naproxen products should not be used concomitantly since they all 420 circulate in the plasma as the naproxen anion. 421 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 422 NAPROSYN Suspension cannot be expected to substitute for corticosteroids 423 or to treat corticosteroid insufficiency. Abrupt discontinuation of 424 corticosteroids may lead to disease exacerbation. Patients on prolonged 425 corticosteroid therapy should have their therapy tapered slowly if a decision is 426 made to discontinue corticosteroids and the patient should be observed closely 427 for any evidence of adverse effects, including adrenal insufficiency and 428 exacerbation of symptoms of arthritis. 429 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 13 Patients with initial hemoglobin values of 10 g or less who are to receive long- 430 term therapy should have hemoglobin values determined periodically. 431 The pharmacological activity of NAPROSYN, EC-NAPROSYN, 432 ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever 433 and inflammation may diminish the utility of these diagnostic signs in 434 detecting complications of presumed noninfectious, noninflammatory painful 435 conditions. 436 Because of adverse eye findings in animal studies with drugs of this class, it is 437 recommended that ophthalmic studies be carried out if any change or 438 disturbance in vision occurs. 439 Hepatic Effects 440 Borderline elevations of one or more liver tests may occur in up to 15% of 441 patients taking NSAIDs including NAPROSYN, EC-NAPROSYN, 442 ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic 443 abnormalities may be the result of hypersensitivity rather than direct toxicity. 444 These laboratory abnormalities may progress, may remain essentially 445 unchanged, or may be transient with continued therapy. The SGPT (ALT) test 446 is probably the most sensitive indicator of liver dysfunction. Notable 447 elevations of ALT or AST (approximately three or more times the upper limit 448 of normal) have been reported in approximately 1% of patients in clinical 449 trials with NSAIDs. In addition, rare cases of severe hepatic reactions, 450 including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic 451 failure, some of them with fatal outcomes have been reported. 452 A patient with symptoms and/or signs suggesting liver dysfunction, or in 453 whom an abnormal liver test has occurred, should be evaluated for evidence 454 of the development of more severe hepatic reaction while on therapy with 455 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 456 NAPROSYN Suspension. 457 If clinical signs and symptoms consistent with liver disease develop, or if 458 systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC- 459 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension 460 should be discontinued. 461 Chronic alcoholic liver disease and probably other diseases with decreased or 462 abnormal plasma proteins (albumin) reduce the total plasma concentration of 463 naproxen, but the plasma concentration of unbound naproxen is increased. 464 Caution is advised when high doses are required and some adjustment of 465 dosage may be required in these patients. It is prudent to use the lowest 466 effective dose. 467 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 14 Hematological Effects 468 Anemia is sometimes seen in patients receiving NSAIDs, including 469 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 470 NAPROSYN Suspension. This may be due to fluid retention, occult or gross 471 GI blood loss, or an incompletely described effect upon erythropoiesis. 472 Patients on long-term treatment with NSAIDs, including NAPROSYN, EC- 473 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, 474 should have their hemoglobin or hematocrit checked if they exhibit any signs 475 or symptoms of anemia. 476 NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding 477 time in some patients. Unlike aspirin, their effect on platelet function is 478 quantitatively less, of shorter duration, and reversible. Patients receiving either 479 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 480 NAPROSYN Suspension who may be adversely affected by alterations in 481 platelet function, such as those with coagulation disorders or patients 482 receiving anticoagulants, should be carefully monitored. 483 Preexisting Asthma 484 Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in 485 patients with aspirin-sensitive asthma has been associated with severe 486 bronchospasm, which can be fatal. Since cross reactivity, including 487 bronchospasm, between aspirin and other nonsteroidal anti-inflammatory 488 drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC- 489 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension 490 should not be administered to patients with this form of aspirin sensitivity and 491 should be used with caution in patients with preexisting asthma. 492 Information for Patients 493 Patients should be informed of the following information before initiating 494 therapy with an NSAID and periodically during the course of ongoing 495 therapy. Patients should also be encouraged to read the NSAID 496 Medication Guide that accompanies each prescription dispensed. 497 1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 498 NAPROSYN Suspension, like other NSAIDs, may cause serious CV side 499 effects, such as MI or stroke, which may result in hospitalization and even 500 death. Although serious CV events can occur without warning symptoms, 501 patients should be alert for the signs and symptoms of chest pain, 502 shortness of breath, weakness, slurring of speech, and should ask for 503 medical advice when observing any indicative sign or symptoms. Patients 504 should be apprised of the importance of this follow-up (see WARNINGS: 505 Cardiovascular Effects). 506 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 15 2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 507 NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort 508 and, rarely, serious GI side effects, such as ulcers and bleeding, which 509 may result in hospitalization and even death. Although serious GI tract 510 ulcerations and bleeding can occur without warning symptoms, patients 511 should be alert for the signs and symptoms of ulcerations and bleeding, 512 and should ask for medical advice when observing any indicative sign or 513 symptoms including epigastric pain, dyspepsia, melena, and hematemesis. 514 Patients should be apprised of the importance of this follow-up (see 515 WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, 516 and Perforation). 517 3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 518 NAPROSYN Suspension, like other NSAIDs, can cause serious skin side 519 effects such as exfoliative dermatitis, SJS, and TEN, which may result in 520 hospitalizations and even death. Although serious skin reactions may 521 occur without warning, patients should be alert for the signs and 522 symptoms of skin rash and blisters, fever, or other signs of 523 hypersensitivity such as itching, and should ask for medical advice when 524 observing any indicative signs or symptoms. Patients should be advised to 525 stop the drug immediately if they develop any type of rash and contact 526 their physicians as soon as possible. 527 4. Patients should promptly report signs or symptoms of unexplained weight 528 gain or edema to their physicians. 529 5. Patients should be informed of the warning signs and symptoms of 530 hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper 531 quadrant tenderness, and “flu-like” symptoms). If these occur, patients 532 should be instructed to stop therapy and seek immediate medical therapy. 533 6. Patients should be informed of the signs of an anaphylactoid reaction (eg, 534 difficulty breathing, swelling of the face or throat). If these occur, patients 535 should be instructed to seek immediate emergency help (see 536 WARNINGS). 537 7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, 538 ANAPROX, ANAPROX DS and NAPROSYN Suspension should be 539 avoided because it may cause premature closure of the ductus arteriosus. 540 8. Caution should be exercised by patients whose activities require alertness 541 if they experience drowsiness, dizziness, vertigo or depression during 542 therapy with naproxen. 543 Laboratory Tests 544 Because serious GI tract ulcerations and bleeding can occur without warning 545 symptoms, physicians should monitor for signs or symptoms of GI bleeding. 546 Patients on long-term treatment with NSAIDs should have their CBC and a 547 chemistry profile checked periodically. If clinical signs and symptoms 548 consistent with liver or renal disease develop, systemic manifestations occur 549 (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, 550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 16 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 551 NAPROSYN Suspension should be discontinued. 552 Drug Interactions 553 ACE-inhibitors 554 Reports suggest that NSAIDs may diminish the antihypertensive effect of 555 ACE-inhibitors. This interaction should be given consideration in patients 556 taking NSAIDs concomitantly with ACE-inhibitors. 557 Antacids and Sucralfate 558 Concomitant administration of some antacids (magnesium oxide or aluminum 559 hydroxide) and sucralfate can delay the absorption of naproxen. 560 Aspirin 561 When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX 562 DS or NAPROSYN Suspension is administered with aspirin, its protein 563 binding is reduced, although the clearance of free NAPROSYN, EC- 564 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is 565 not altered. The clinical significance of this interaction is not known; 566 however, as with other NSAIDs, concomitant administration of naproxen and 567 naproxen sodium and aspirin is not generally recommended because of the 568 potential of increased adverse effects. 569 Cholestyramine 570 As with other NSAIDs, Cconcomitant administration of cholestyramine can 571 delay the absorption of naproxen. 572 Diuretics 573 Clinical studies, as well as postmarketing observations, have shown that 574 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 575 NAPROSYN Suspension can reduce the natriuretic effect of furosemide and 576 thiazides in some patients. This response has been attributed to inhibition of 577 renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the 578 patient should be observed closely for signs of renal failure (see 579 WARNINGS: Renal Effects), as well as to assure diuretic efficacy. 580 Lithium 581 NSAIDs have produced an elevation of plasma lithium levels and a reduction 582 in renal lithium clearance. The mean minimum lithium concentration 583 increased 15% and the renal clearance was decreased by approximately 20%. 584 These effects have been attributed to inhibition of renal prostaglandin 585 synthesis by the NSAID. Thus, when NSAIDs and lithium are administered 586 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 17 concurrently, subjects should be observed carefully for signs of lithium 587 toxicity. 588 Methotrexate 589 NSAIDs have been reported to competitively inhibit methotrexate 590 accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other 591 nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular 592 secretion of methotrexate in an animal model. This may indicate that they 593 could enhance the toxicity of methotrexate. Caution should be used when 594 NSAIDs are administered concomitantly with methotrexate. 595 Warfarin 596 The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that 597 users of both drugs together have a risk of serious GI bleeding higher than 598 users of either drug alone. No significant interactions have been observed in 599 clinical studies with naproxen and coumarin-type anticoagulants. However, 600 caution is advised since interactions have been seen with other nonsteroidal 601 agents of this class. The free fraction of warfarin may increase substantially in 602 some subjects and naproxen interferes with platelet function. 603 Other Information Concerning Drug Interactions 604 Naproxen is highly bound to plasma albumin; it thus has a theoretical 605 potential for interaction with other albumin-bound drugs such as coumarin- 606 type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. 607 Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or 608 sulphonylurea should be observed for adjustment of dose if required. 609 Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the 610 antihypertensive effect of propranolol and other beta-blockers. 611 Probenecid given concurrently increases naproxen anion plasma levels and 612 extends its plasma half-life significantly. 613 Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive 614 antacid therapy, concomitant administration of EC-NAPROSYN is not 615 recommended. 616 Drug/Laboratory Test Interaction 617 Naproxen may decrease platelet aggregation and prolong bleeding time. This 618 effect should be kept in mind when bleeding times are determined. 619 The administration of naproxen may result in increased urinary values for 17- 620 ketogenic steroids because of an interaction between the drug and/or its 621 metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy- 622 corticosteroid measurements (Porter-Silber test) do not appear to be 623 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 18 artifactually altered, it is suggested that therapy with naproxen be temporarily 624 discontinued 72 hours before adrenal function tests are performed if the 625 Porter-Silber test is to be used. 626 Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic 627 acid (5HIAA). 628 Carcinogenesis 629 A 2-year study was performed in rats to evaluate the carcinogenic potential of 630 naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). 631 The maximum dose used was 0.28 times the systemic exposure to humans at 632 the recommended dose. No evidence of tumorigenicity was found. 633 Pregnancy 634 Teratogenic Effects 635 Pregnancy Category C 636 Reproduction studies have been performed in rats at 20 mg/kg/day 637 (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 638 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and 639 mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic 640 exposure) with no evidence of impaired fertility or harm to the fetus due to the 641 drug. However, animal reproduction studies are not always predictive of 642 human response. There are no adequate and well-controlled studies in 643 pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX 644 DS and NAPROSYN Suspension should be used in pregnancy only if the 645 potential benefit justifies the potential risk to the fetus. 646 Nonteratogenic Effects 647 There is some evidence to suggest that when inhibitors of prostaglandin 648 synthesis are used to delay preterm labor there is an increased risk of neonatal 649 complications such as necrotizing enterocolitis, patent ductus arteriosus and 650 intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay 651 parturition has been associated with persistent pulmonary hypertension, renal 652 dysfunction and abnormal prostaglandin E levels in preterm infants. Because 653 of the known effects of nonsteroidal anti-inflammatory drugs on the fetal 654 cardiovascular system (closure of ductus arteriosus), use during pregnancy 655 (particularly late pregnancy) should be avoided. 656 Labor and Delivery 657 In rat studies with NSAIDs, as with other drugs known to inhibit 658 prostaglandin synthesis, an increased incidence of dystocia, delayed 659 parturition, and decreased pup survival occurred. Naproxen-containing 660 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 19 products are not recommended in labor and delivery because, through its 661 prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal 662 circulation and inhibit uterine contractions, thus increasing the risk of uterine 663 hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX, 664 ANAPROX DS and NAPROSYN Suspension on labor and delivery in 665 pregnant women are unknown. 666 Nursing Mothers 667 The naproxen anion has been found in the milk of lactating women at a 668 concentration equivalent to approximately 1% of maximum naproxen 669 concentration in plasma. Because of the possible adverse effects of 670 prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be 671 avoided. 672 Pediatric Use 673 Safety and effectiveness in pediatric patients below the age of 2 years have 674 not been established. Pediatric dosing recommendations for juvenile arthritis 675 are based on well-controlled studies (see DOSAGE AND 676 ADMINISTRATION). There are no adequate effectiveness or dose-response 677 data for other pediatric conditions, but the experience in juvenile arthritis and 678 other use experience have established that single doses of 2.5 to 5 mg/kg (as 679 naproxen suspension, see DOSAGE AND ADMINISTRATION), with total 680 daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients 681 over 2 years of age. 682 Geriatric Use 683 Studies indicate that although total plasma concentration of naproxen is 684 unchanged, the unbound plasma fraction of naproxen is increased in the 685 elderly. Caution is advised when high doses are required and some adjustment 686 of dosage may be required in elderly patients. As with other drugs used in the 687 elderly, it is prudent to use the lowest effective dose. 688 Experience indicates that geriatric patients may be particularly sensitive to 689 certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or 690 debilitated patients seem to tolerate peptic ulceration or bleeding less well 691 when these events do occur. Most spontaneous reports of fatal GI events are in 692 the geriatric population (see WARNINGS). 693 Naproxen is known to be substantially excreted by the kidney, and the risk of 694 toxic reactions to this drug may be greater in patients with impaired renal 695 function. Because elderly patients are more likely to have decreased renal 696 function, care should be taken in dose selection, and it may be useful to 697 monitor renal function. Geriatric patients may be at a greater risk for the 698 development of a form of renal toxicity precipitated by reduced prostaglandin 699 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 20 formation during administration of nonsteroidal anti-inflammatory drugs (see 700 WARNINGS: Renal Effects). 701 ADVERSE REACTIONS 702 Adverse reactions reported in controlled clinical trials in 960 patients treated 703 for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions 704 in patients treated chronically were reported 2 to 10 times more frequently 705 than they were in short-term studies in the 962 patients treated for mild to 706 moderate pain or for dysmenorrhea. The most frequent complaints reported 707 related to the gastrointestinal tract. 708 A clinical study found gastrointestinal reactions to be more frequent and more 709 severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen 710 compared to those taking 750 mg naproxen (see CLINICAL 711 PHARMACOLOGY). 712 In controlled clinical trials with about 80 pediatric patients and in well- 713 monitored, open-label studies with about 400 pediatric patients with juvenile 714 arthritis treated with naproxen, the incidence of rash and prolonged bleeding 715 times were increased, the incidence of gastrointestinal and central nervous 716 system reactions were about the same, and the incidence of other reactions 717 were lower in pediatric patients than in adults. 718 In patients taking naproxen in clinical trials, the most frequently reported 719 adverse experiences in approximately 1% to 10% of patients are: 720 Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, 721 nausea, constipation, diarrhea, dyspepsia, stomatitis 722 Central Nervous System: headache, dizziness, drowsiness, 723 lightheadedness, vertigo 724 Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, 725 purpura 726 Special Senses: tinnitus, visual disturbances, hearing disturbances 727 Cardiovascular: edema, palpitations 728 General: dyspnea, thirst 729 *Incidence of reported reaction between 3% and 9%. Those reactions 730 occurring in less than 3% of the patients are unmarked. 731 In patients taking NSAIDs, the following adverse experiences have also been 732 reported in approximately 1% to 10% of patients. 733 Gastrointestinal (GI) Experiences, including: flatulence, gross 734 bleeding/perforation, GI ulcers (gastric/duodenal), vomiting 735 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 21 General: abnormal renal function, anemia, elevated liver enzymes, increased 736 bleeding time, rashes 737 The following are additional adverse experiences reported in <1% of patients 738 taking naproxen during clinical trials and through postmarketing reports. 739 Those adverse reactions observed through postmarketing reports are italicized. 740 Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual 741 disorders, pyrexia (chills and fever) 742 Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary 743 edema 744 Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, 745 jaundice, pancreatitis, vomiting, colitis, abnormal liver function tests, 746 nonpeptic gastrointestinal ulceration, ulcerative stomatitis, esophagitis, peptic 747 ulceration, hepatitis (some cases have been fatal) 748 Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases 749 have been fatal) 750 Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, 751 agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia 752 Metabolic and Nutritional: hyperglycemia, hypoglycemia 753 Nervous System: inability to concentrate, depression, dream abnormalities, 754 insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive 755 dysfunction, convulsions 756 Respiratory: eosinophilic pneumonitis, asthma 757 Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, 758 erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, 759 pustular reaction, systemic lupus erythematoses, Stevens-Johnson syndrome, 760 photosensitive dermatitis, photosensitivity reactions, including rare cases 761 resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis 762 bullosa. If skin fragility, blistering or other symptoms suggestive of 763 pseudoporphyria occur, treatment should be discontinued and the patient 764 monitored. 765 Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar 766 optic neuritis, papilledema 767 Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial 768 nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary 769 necrosis, raised serum creatinine 770 Reproduction (female): infertility 771 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 22 In patients taking NSAIDs, the following adverse experiences have also been 772 reported in <1% of patients. 773 Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite 774 changes, death 775 Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, 776 hypotension, myocardial infarction 777 Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, 778 glossitis, hepatitis, eructation, liver failure 779 Hepatobiliary: hepatitis, liver failure 780 Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia 781 Metabolic and Nutritional: weight changes 782 Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, 783 somnolence, tremors, convulsions, coma, hallucinations 784 Respiratory: asthma, respiratory depression, pneumonia 785 Dermatologic: exfoliative dermatitis 786 Special Senses: blurred vision, conjunctivitis 787 Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria 788 OVERDOSAGE 789 Significant naproxen overdosage may be characterized by lethargy, dizziness, 790 drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, 791 nausea, transient alterations in liver function, hypoprothrombinemia, renal 792 dysfunction, metabolic acidosis, apnea, disorientation or vomiting. 793 Gastrointestinal bleeding can occur. Hypertension, acute renal failure, 794 respiratory depression, and coma may occur, but are rare. Anaphylactoid 795 reactions have been reported with therapeutic ingestion of NSAIDs, and may 796 occur following an overdose. Because naproxen sodium may be rapidly 797 absorbed, high and early blood levels should be anticipated. A few patients 798 have experienced convulsions, but it is not clear whether or not these were 799 drug-related. It is not known what dose of the drug would be life threatening. 800 The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 801 mg/kg in hamsters, and greater than 1000 mg/kg in dogs. 802 Patients should be managed by symptomatic and supportive care following a 803 NSAID overdose. There are no specific antidotes. Hemodialysis does not 804 decrease the plasma concentration of naproxen because of the high degree of 805 its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 806 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients 807 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 23 seen within 4 hours of ingestion with symptoms or following a large overdose. 808 Forced diuresis, alkalinization of urine or hemoperfusion may not be useful 809 due to high protein binding. 810 DOSAGE AND ADMINISTRATION 811 Carefully consider the potential benefits and risks of NAPROSYN, EC- 812 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and 813 other treatment options before deciding to use NAPROSYN, EC- 814 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. 815 Use the lowest effective dose for the shortest duration consistent with 816 individual patient treatment goals (see WARNINGS). 817 After observing the response to initial therapy with NAPROSYN, EC- 818 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the 819 dose and frequency should be adjusted to suit an individual patient’s needs. 820 Different dose strengths and formulations (ie, tablets, suspension) of the 821 drug are not necessarily bioequivalent. This difference should be taken 822 into consideration when changing formulation. 823 Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, 824 ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they 825 have pharmacokinetic differences that may affect onset of action. Onset of 826 pain relief can begin within 30 minutes in patients taking naproxen sodium 827 and within 1 hour in patients taking naproxen. Because EC-NAPROSYN 828 dissolves in the small intestine rather than in the stomach, the absorption of 829 the drug is delayed compared to the other naproxen formulations (see 830 CLINICAL PHARMACOLOGY). 831 The recommended strategy for initiating therapy is to choose a formulation 832 and a starting dose likely to be effective for the patient and then adjust the 833 dosage based on observation of benefit and/or adverse events. A lower dose 834 should be considered in patients with renal or hepatic impairment or in elderly 835 patients (see WARNINGS and PRECAUTIONS). 836 Geriatric Patients 837 Studies indicate that although total plasma concentration of naproxen is 838 unchanged, the unbound plasma fraction of naproxen is increased in the 839 elderly. Caution is advised when high doses are required and some adjustment 840 of dosage may be required in elderly patients. As with other drugs used in the 841 elderly, it is prudent to use the lowest effective dose. 842 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 24 Patients With Moderate to Severe Renal Impairment 843 Naproxen-containing products are not recommended for use in patients with 844 moderate to severe and severe renal impairment (creatinine clearance <30 845 mL/min) (see WARNINGS: Renal Effects). 846 Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis 847 NAPROSYN 250 mg or 375 mg or 500 mg twice daily twice daily twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp) or 375 mg (15 mL/3 tsp) or 500 mg (20 mL/4 tsp) twice daily twice daily twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet 848 should not be broken, crushed or chewed during ingestion. NAPROSYN 849 Suspension should be shaken gently before use. 850 During long-term administration, the dose of naproxen may be adjusted up or 851 down depending on the clinical response of the patient. A lower daily dose 852 may suffice for long-term administration. The morning and evening doses do 853 not have to be equal in size and the administration of the drug more frequently 854 than twice daily is not necessary. 855 In patients who tolerate lower doses well, the dose may be increased to 856 naproxen 1500 mg/day for limited periods of up to 6 months when a higher 857 level of anti-inflammatory/analgesic activity is required. When treating such 858 patients with naproxen 1500 mg/day, the physician should observe sufficient 859 increased clinical benefits to offset the potential increased risk. The morning 860 and evening doses do not have to be equal in size and administration of the 861 drug more frequently than twice daily does not generally make a difference in 862 response (see CLINICAL PHARMACOLOGY). 863 Juvenile Arthritis 864 The use of NAPROSYN Suspension is recommended for juvenile arthritis in 865 children 2 years or older because it allows for more flexible dose titration 866 based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day 867 produced plasma levels of naproxen similar to those seen in adults taking 500 868 mg of naproxen (see CLINICAL PHARMACOLOGY). 869 The recommended total daily dose of naproxen is approximately 10 mg/kg 870 given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup 871 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 25 marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the 872 NAPROSYN Suspension. The following table may be used as a guide for 873 dosing of NAPROSYN Suspension: 874 Patient’s Weight Dose Administered as 875 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 876 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 877 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily 878 Management of Pain, Primary Dysmenorrhea, and Acute 879 Tendonitis and Bursitis 880 The recommended starting dose is 550 mg of naproxen sodium as 881 ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg 882 every 6 to 8 hours as required. The initial total daily dose should not exceed 883 1375 mg of naproxen sodium. Thereafter, the total daily dose should not 884 exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is 885 more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the 886 management of acute painful conditions when prompt onset of pain relief is 887 desired. NAPROSYN may also be used but EC-NAPROSYN is not 888 recommended for initial treatment of acute pain because absorption of 889 naproxen is delayed compared to other naproxen-containing products (see 890 CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). 891 Acute Gout 892 The recommended starting dose is 750 mg of NAPROSYN followed by 250 893 mg every 8 hours until the attack has subsided. ANAPROX may also be used 894 at a starting dose of 825 mg followed by 275 mg every 8 hours. EC- 895 NAPROSYN is not recommended because of the delay in absorption (see 896 CLINICAL PHARMACOLOGY). 897 HOW SUPPLIED 898 NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR 899 LE 250 on one side and scored on the other. Packaged in light-resistant bottles 900 of 100. 901 100’s (bottle): NDC 0004-6313-01. 902 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. 903 Packaged in light-resistant bottles of 100. 904 100’s (bottle): NDC 0004-6314-01. 905 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and 906 scored on the other. Packaged in light-resistant bottles of 100. 907 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 26 100’s (bottle): NDC 0004-6316-01. 908 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light- 909 resistant containers. 910 NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 911 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 912 0004-0028-28). 913 Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). 914 Dispense in light-resistant containers. Shake gently before use. 915 EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, capsule-shaped, 916 imprinted with EC-NAPROSYN on one side and 375 on the other. Packaged 917 in light-resistant bottles of 100. 918 100’s (bottle): NDC 0004-6415-01. 919 500 mg: white, capsule-shaped, imprinted with EC-NAPROSYN on one side 920 and 500 on the other. Packaged in light-resistant bottles of 100. 921 100’s (bottle): NDC 0004-6416-01. 922 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light- 923 resistant containers. 924 ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, 925 engraved with NPS-275 on one side. Packaged in bottles of 100. 926 100’s (bottle): NDC 0004-6202-01. 927 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 928 ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong- 929 shaped, engraved with NPS 550 on one side and scored on both sides. 930 Packaged in bottles of 100. 931 100’s (bottle): NDC 0004-6203-01. 932 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 933 Revised: January 2006Month Year 934 935 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 27 Medication Guide 936 for 937 Non-steroidal Anti-Inflammatory Drugs (NSAIDs) 938 (See the end of this Medication Guide for a list of prescription NSAID 939 medicines.) 940 941 What is the most important information I should know about medicines 942 called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? 943 NSAID medicines may increase the chance of a heart attack or 944 stroke that can lead to death. This chance increases: 945 • with longer use of NSAID medicines 946 • in people who have heart disease 947 948 NSAID medicines should never be used right before or after a 949 heart surgery called a “coronary artery bypass graft (CABG).” 950 NSAID medicines can cause ulcers and bleeding in the stomach 951 and intestines at any time during treatment. Ulcers and bleeding: 952 • can happen without warning symptoms 953 • may cause death 954 955 The chance of a person getting an ulcer or bleeding increases 956 with: 957 • taking medicines called “corticosteroids” and 958 “anticoagulants” 959 • longer use 960 • smoking 961 • drinking alcohol 962 • older age 963 • having poor health 964 965 NSAID medicines should only be used: 966 • exactly as prescribed 967 • at the lowest dose possible for your treatment 968 • for the shortest time needed 969 970 What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? 971 NSAID medicines are used to treat pain and redness, swelling, and heat 972 (inflammation) from medical conditions such as: 973 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 28 • different types of arthritis 974 • menstrual cramps and other types of short-term pain 975 976 Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? 977 Do not take an NSAID medicine: 978 • if you had an asthma attack, hives, or other allergic reaction with 979 aspirin or any other NSAID medicine 980 • for pain right before or after heart bypass surgery 981 982 Tell your healthcare provider: 983 • about all of your medical conditions. 984 • about all of the medicines you take. NSAIDs and some other 985 medicines can interact with each other and cause serious side 986 effects. Keep a list of your medicines to show to your 987 healthcare provider and pharmacist. 988 • if you are pregnant. NSAID medicines should not be used by 989 pregnant women late in their pregnancy. 990 • if you are breastfeeding. Talk to your doctor. 991 992 What are the possible side effects of Non-Steroidal Anti-Inflammatory 993 Drugs (NSAIDs)? 994 Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness 995 Get emergency help right away if you have any of the following 996 symptoms: 997 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 29 • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat 998 Stop your NSAID medicine and call your healthcare provider right away 999 if you have any of the following symptoms: 1000 • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet 1001 These are not all the side effects with NSAID medicines. Talk to your 1002 healthcare provider or pharmacist for more information about NSAID 1003 medicines. 1004 Other information about Non-Steroidal Anti-Inflammatory Drugs 1005 (NSAIDs): 1006 • Aspirin is an NSAID medicine but it does not increase the chance of a 1007 heart attack. Aspirin can cause bleeding in the brain, stomach, and 1008 intestines. Aspirin can also cause ulcers in the stomach and intestines. 1009 • Some of these NSAID medicines are sold in lower doses without a 1010 prescription (over-the-counter). Talk to your healthcare provider before 1011 using over-the-counter NSAIDs for more than 10 days. 1012 1013 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 30 NSAID medicines that need a prescription 1014 Generic Name Tradename Celecoxib Celebrex® Diclofenac Cataflam®, Voltaren®, Arthrotec™ (combined with misoprostol) Diflunisal Dolobid® Etodolac Lodine®, Lodine®XL Fenoprofen Nalfon®, Nalfon®200 Flurbirofen Ansaid® Ibuprofen Motrin®, Tab-Profen®, Vicoprofen® (combined with hydrocodone), Combunox™ (combined with oxycodone) Indomethacin Indocin®, Indocin®SR, Indo-Lemmon™, Indomethagan™ Ketoprofen Oruvail® Ketorolac Toradol® Mefenamic Acid Ponstel® Meloxicam Mobic® Nabumetone Relafen® Naproxen Naprosyn®, Anaprox®, Anaprox®DS, EC-Naprosyn®, Naprelan®, Naprapac® (copackaged with lansoprazole) Oxaprozin Daypro® Piroxicam Feldene® Sulindac Clinoril® Tolmetin Tolectin®, Tolectin DS®, Tolectin®600 1015 Issued: January 2006 1016 This Medication Guide has been approved by the U.S. Food and Drug 1017 Administration. 1018 1019 All registered trademarks in this document are the property of their respective 1020 owners. 1021 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 31 Distributed by: 1022 1023 27899102xxxxxxxx 1024 Copyright © 1999-2006 by Roche Laboratories Inc. All rights reserved. 1025 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/ --------------------- Sharon Hertz 3/10/2006 03:59:36 PM Signing for Bob Rappaport, M.D. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:07.838874	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020067s010,018965s013,018164s055, 017581s105lbl.pdf', 'application_number': 18965, 'submission_type': 'SUPPL ', 'submission_number': 13}
11,390	EC-NAPROSYN (naproxen delayed-release tablets) NAPROSYN (naproxen tablets) ANAPROX/ANAPROX DS (naproxen sodium tablets) NAPROSYN (naproxen suspension) Rx only Cardiovascular Risk  NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).  Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk  NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). DESCRIPTION Naproxen is a proprionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-- methyl-2-naphthaleneacetic acid and (S)-6-methoxy--methyl-2- naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen sodium have the following structures, respectively: Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of C14H13NaO3. Naproxen is an odorless, white to off-white crystalline substance. It is lipid- soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. 1 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of naproxen, pink tablets containing 375 mg of naproxen and yellow tablets containing 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, iron oxides, povidone and magnesium stearate. EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric- coated white tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified water. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH 4. ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue tablets containing 550 mg of naproxen sodium for oral administration. The inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Opadry YS-1-4216. NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle containing sucrose, magnesium aluminum silicate, sorbitol solution and sodium chloride (39 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified water. The pH of the suspension ranges from 2.2 to 3.7. CLINICAL PHARMACOLOGY Pharmacodynamics Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different 2 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. Absorption Immediate Release After administration of NAPROSYN tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours. Delayed Release EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC- NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC-NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there were no differences in total absorption as measured by Cmax and AUC: EC-NAPROSYN* 500 mg bid NAPROSYN* 500 mg bid Cmax (µg/mL) 94.9 (18%) 97.4 (13%) Tmax (hours) 4 (39%) 1.9 (61%) AUC0–12 hr (µg·hr/mL) 845 (20%) 767 (15%) Mean value (coefficient of variation) 3 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Antacid Effects When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly. Food Effects When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax). Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS: Nursing Mothers). Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate (see WARNINGS: Renal Effects). 4 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Special Populations Pediatric Patients In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND ADMINISTRATION) were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN has not been studied in subjects under the age of 18. Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Race Pharmacokinetic differences due to race have not been studied. Hepatic Insufficiency Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Renal Insufficiency Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Effects). CLINICAL STUDIES General Information Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute 5 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (eg, decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater 6 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) improvement over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These studies indicated that EC- NAPROSYN and NAPROSYN showed no significant differences in efficacy or safety and had similar prevalence of minor GI complaints. Individual patients, however, may find one formulation preferable to the other. Five hundred and fifty-three patients received EC-NAPROSYN during long- term open-label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use. Geriatric Patients The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use 7 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is indicated:  For the relief of the signs and symptoms of rheumatoid arthritis  For the relief of the signs and symptoms of osteoarthritis  For the relief of the signs and symptoms of ankylosing spondylitis  For the relief of the signs and symptoms of juvenile arthritis Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the patient’s weight. Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is also indicated:  For relief of the signs and symptoms of tendonitis  For relief of the signs and symptoms of bursitis  For relief of the signs and symptoms of acute gout  For the management of pain  For the management of primary dysmenorrhea EC-NAPROSYN is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated in patients with known hypersensitivity to naproxen and naproxen sodium. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma). NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated for the treatment of peri- 8 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS: Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used with caution in 9 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) patients with fluid retention, hypertension, or heart failure. Since each ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of naproxen) of sodium, this should be considered in patients whose overall intake of sodium must be severely restricted. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. 10 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an NSAID or aspirin potentiated the risk of bleeding (see PRECAUTIONS: Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state (see WARNINGS: Advanced Renal Disease). Advanced Renal Disease No information is available from controlled clinical studies regarding the use of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension in patients with advanced renal disease. Therefore, treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is not recommended in these patients with advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close monitoring of the patient’s renal function is advisable and patients should be adequately hydrated. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without 11 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Skin Reactions NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. Patients with initial hemoglobin values of 10 g or less who are to receive long- term therapy should have hemoglobin values determined periodically. The pharmacological activity of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions. 12 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension should be discontinued. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. 13 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: Cardiovascular Effects). 2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation). 14 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (eg, difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. 8. Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be discontinued. Drug Interactions Angiotensin Converting Enzyme (ACE)-inhibitors/Angiotensin Receptor Blockers (ARBs) NSAIDs may diminish the antihypertensive effect of ACE-inhibitors, ARBs, or beta-blockers (including propanolol). Monitor patients taking NSAIDs concomitantly with ACE-inhibitors, ARBs, or beta blockers for changes in blood pressure. 15 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) In addition, in patients who are elderly, volume-depleted (including those on diuretic therapy), or have compromised renal function, co-administration of NSAIDs with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. Monitor these patients closely for signs of worsening renal function Antacids and Sucralfate Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Aspirin When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is administered with aspirin, its protein binding is reduced, although the clearance of free NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of naproxen and naproxen sodium and aspirin is not generally recommended because of the potential of increased adverse effects. Cholestyramine As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen. Diuretics Clinical studies, as well as postmarketing observations, have shown that NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other 16 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. No significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants. However, caution is advised since interactions have been seen with other nonsteroidal agents of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function. Selective Serotonin Reuptake Inhibitors (SSRIs) There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs. Other Information Concerning Drug Interactions Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin- type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of EC-NAPROSYN is not recommended. Drug/Laboratory Test Interaction Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. The administration of naproxen may result in increased urinary values for 17- ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy- corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. 17 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). The maximum dose used was 0.28 times the systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found. Pregnancy Teratogenic Effects Pregnancy Category C Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension on labor and delivery in pregnant women are unknown. 18 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Nursing Mothers The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided. Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND ADMINISTRATION), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. Geriatric Use Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS). Naproxen 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. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs (see WARNINGS: Renal Effects). ADVERSE REACTIONS Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to 19 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen (see CLINICAL PHARMACOLOGY). In controlled clinical trials with about 80 pediatric patients and in well- monitored, open-label studies with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: edema, palpitations General: dyspnea, thirst Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. 20 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease). Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis, asthma Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death 21 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria OVERDOSAGE Symptoms and Signs Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs. Treatment Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding. 22 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient’s needs. Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation. Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the stomach, the absorption of the drug is delayed compared to the other naproxen formulations (see CLINICAL PHARMACOLOGY). The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS). Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Patients With Moderate to Severe Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Effects). 23 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis NAPROSYN 250 mg or 375 mg or 500 mg twice daily twice daily twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp) or 375 mg (15 mL/3 tsp) or 500 mg (20 mL/4 tsp) twice daily twice daily twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. NAPROSYN Suspension should be shaken gently before use. During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY). Juvenile Arthritis The use of NAPROSYN Suspension is recommended for juvenile arthritis in children 2 years or older because it allows for more flexible dose titration based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen (see CLINICAL PHARMACOLOGY). The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing of NAPROSYN Suspension: 24 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Patient’s Weight Dose Administered as 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN may also be used but EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). Acute Gout The recommended starting dose is 750 mg of NAPROSYN followed by 250 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. EC- NAPROSYN is not recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). HOW SUPPLIED NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on one side and scored on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6313-01. 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6314-01. 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6316-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light- resistant containers. 25 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28). Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). Dispense in light-resistant containers. Shake gently before use. EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. Packaged in light- resistant bottles of 100. 100’s (bottle): NDC 0004-6415-01. 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6416-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light- resistant containers. ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with NPS-275 on one side. Packaged in bottles of 100. 100’s (bottle): NDC 0004-6202-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers. ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong- shaped, engraved with NPS 550 on one side and scored on both sides. Packaged in bottles of 100. 100’s (bottle): NDC 0004-6203-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers. Revised: March 2013 26 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Medication Guide for Non-steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:  with longer use of NSAID medicines  in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).” NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:  can happen without warning symptoms  may cause death The chance of a person getting an ulcer or bleeding increases with:  taking medicines called “corticosteroids” and “anticoagulants”  longer use  smoking  drinking alcohol  older age  having poor health NSAID medicines should only be used:  exactly as prescribed  at the lowest dose possible for your treatment  for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? 27 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:  different types of arthritis  menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine:  if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine  for pain right before or after heart bypass surgery Tell your healthcare provider:  about all of your medical conditions.  about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.  if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.  if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include:  heart attack  stroke  high blood pressure  heart failure from body swelling (fluid retention)  kidney problems including kidney failure  bleeding and ulcers in the stomach and intestine  low red blood cells (anemia)  life-threatening skin reactions  life-threatening allergic reactions  liver problems including liver failure  asthma attacks in people who have asthma Other side effects include:  stomach pain  constipation  diarrhea  gas  heartburn  nausea  vomiting  dizziness 28 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Get emergency help right away if you have any of the following symptoms:  shortness of breath or trouble breathing  chest pain  weakness in one part or side of your body  slurred speech  swelling of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:  nausea  more tired or weaker than usual  itching  your skin or eyes look yellow  stomach pain  flu-like symptoms  vomit blood  there is blood in your bowel movement or it is black and sticky like tar  unusual weight gain  skin rash or blisters with fever  swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Genentech at 1-888-835- 2555. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):  Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.  Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. 29 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, LodineXL Fenoprofen Nalfon, Nalfon200 Flurbirofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, IndocinSR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, AnaproxDS, EC-Naprosyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin600 *Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAID, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. This Medication Guide has been approved by the U.S. Food and Drug Administration. Medication Guide Revised: October 2010 All registered trademarks in this document are the property of their respective owners. 30 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 31 ENT/NNT/AST/NNS_210516_PIMG_2012_01_K  Year Genentech, Inc. All rights reserved. Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:08.638615	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017581s111,018164s061,018965s020,020067s018lbl.pdf', 'application_number': 18965, 'submission_type': 'SUPPL ', 'submission_number': 20}
11,389	1 2 EC-NAPROSYN® (naproxen delayed-release tablets) 3 NAPROSYN® (naproxen tablets) 4 ANAPROX®/ANAPROX® DS (naproxen sodium tablets) 5 NAPROSYN® (naproxen suspension) Roche Logo 6 Rx only Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). • Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). 7 DESCRIPTION 8 Naproxen is a proprionic acid derivative related to the arylacetic acid group of 9 nonsteroidal anti-inflammatory drugs. 10 The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α 11 methyl-2-naphthaleneacetic acid and (S)-6-methoxy-α-methyl-2 12 naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen 13 sodium have the following structures, respectively: Chemical Structure 15 Naproxen has a molecular weight of 230.26 and a molecular formula of 16 C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a 17 molecular formula of C14H13NaO3. 18 Naproxen is an odorless, white to off-white crystalline substance. It is lipid 19 soluble, practically insoluble in water at low pH and freely soluble in water at 20 high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 21 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely 22 soluble in water at neutral pH. 23 NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 24 mg of naproxen, pink tablets containing 375 mg of naproxen and yellow 25 tablets containing 500 mg of naproxen for oral administration. The inactive 26 ingredients are croscarmellose sodium, iron oxides, povidone and magnesium 27 stearate. 28 EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric 29 coated white tablets containing 375 mg of naproxen and 500 mg of naproxen 30 for oral administration. The inactive ingredients are croscarmellose sodium, 31 povidone and magnesium stearate. The enteric coating dispersion contains 32 methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and 33 purified water. The dissolution of this enteric-coated naproxen tablet is pH 34 dependent with rapid dissolution above pH 6. There is no dissolution below 35 pH 4. 36 ANAPROX (naproxen sodium tablets) is available as blue tablets containing 37 275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is 38 available as dark blue tablets containing 550 mg of naproxen sodium for oral 39 administration. The inactive ingredients are magnesium stearate, 40 microcrystalline cellulose, povidone and talc. The coating suspension for the 41 ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910, 42 Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The 43 coating suspension for the ANAPROX DS 550 mg tablet may contain 44 hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene 45 glycol 8000 or Opadry YS-1-4216. 46 NAPROSYN (naproxen suspension) is available as a light orange-colored 47 opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle 48 containing sucrose, magnesium aluminum silicate, sorbitol solution and 49 sodium chloride (39 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C 50 Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified 51 water. The pH of the suspension ranges from 2.2 to 3.7. 52 CLINICAL PHARMACOLOGY 53 Pharmacodynamics 54 Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic 55 and antipyretic properties. The sodium salt of naproxen has been developed as 56 a more rapidly absorbed formulation of naproxen for use as an analgesic. The 57 mechanism of action of the naproxen anion, like that of other NSAIDs, is not 58 completely understood but may be related to prostaglandin synthetase 59 inhibition. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 60 Pharmacokinetics 61 Naproxen and naproxen sodium are rapidly and completely absorbed from the 62 gastrointestinal tract with an in vivo bioavailability of 95%. The different 63 dosage forms of NAPROSYN are bioequivalent in terms of extent of 64 absorption (AUC) and peak concentration (Cmax); however, the products do 65 differ in their pattern of absorption. These differences between naproxen 66 products are related to both the chemical form of naproxen used and its 67 formulation. Even with the observed differences in pattern of absorption, the 68 elimination half-life of naproxen is unchanged across products ranging from 69 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and 70 the degree of naproxen accumulation is consistent with this half-life. This 71 suggests that the differences in pattern of release play only a negligible role in 72 the attainment of steady-state plasma levels. 73 Absorption 74 Immediate Release 75 After administration of NAPROSYN tablets, peak plasma levels are attained 76 in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels 77 are attained in 1 to 2 hours. The difference in rates between the two products 78 is due to the increased aqueous solubility of the sodium salt of naproxen used 79 in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN 80 Suspension are attained in 1 to 4 hours. 81 Delayed Release 82 EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier 83 to disintegration in the acidic environment of the stomach and to lose integrity 84 in the more neutral environment of the small intestine. The enteric polymer 85 coating selected for EC-NAPROSYN dissolves above pH 6. When EC 86 NAPROSYN was given to fasted subjects, peak plasma levels were attained 87 about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo 88 study in man using radiolabeled EC-NAPROSYN tablets demonstrated that 89 EC-NAPROSYN dissolves primarily in the small intestine rather than in the 90 stomach, so the absorption of the drug is delayed until the stomach is emptied. 91 When EC-NAPROSYN and NAPROSYN were given to fasted subjects 92 (n=24) in a crossover study following 1 week of dosing, differences in time to 93 peak plasma levels (Tmax) were observed, but there were no differences in total 94 absorption as measured by Cmax and AUC: 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) EC-NAPROSYN* 500 mg bid NAPROSYN* 500 mg bid Cmax (µg/mL) Tmax (hours) AUC0–12 hr (µg·hr/mL) 94.9 (18%) 4 (39%) 845 (20%) 97.4 (13%) 1.9 (61%) 767 (15%) 95 Mean value (coefficient of variation) 96 Antacid Effects 97 When EC-NAPROSYN was given as a single dose with antacid (54 mEq 98 buffering capacity), the peak plasma levels of naproxen were unchanged, but 99 the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with 100 antacid 5 hours), although not significantly. 101 Food Effects 102 When EC-NAPROSYN was given as a single dose with food, peak plasma 103 levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). 104 Residence time in the small intestine until disintegration was independent of 105 food intake. The presence of food prolonged the time the tablets remained in 106 the stomach, time to first detectable serum naproxen levels, and time to 107 maximal naproxen levels (Tmax), but did not affect peak naproxen levels 108 (Cmax). 109 Distribution 110 Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels 111 naproxen is greater than 99% albumin-bound. At doses of naproxen greater 112 than 500 mg/day there is less than proportional increase in plasma levels due 113 to an increase in clearance caused by saturation of plasma protein binding at 114 higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 115 1500 mg daily doses of naproxen, respectively). The naproxen anion has been 116 found in the milk of lactating women at a concentration equivalent to 117 approximately 1% of maximum naproxen concentration in plasma (see 118 PRECAUTIONS: Nursing Mothers). 119 Metabolism 120 Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, 121 and both parent and metabolites do not induce metabolizing enzymes. Both 122 naproxen and 6-0-desmethyl naproxen are further metabolized to their 123 respective acylglucuronide conjugated metabolites. 124 Excretion 125 The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the 126 naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 127 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 128 half-life of the naproxen anion in humans ranges from 12 to 17 hours. The 129 corresponding half-lives of both naproxen’s metabolites and conjugates are 130 shorter than 12 hours, and their rates of excretion have been found to coincide 131 closely with the rate of naproxen disappearance from the plasma. Small 132 amounts, 3% or less of the administered dose, are excreted in the feces. In 133 patients with renal failure metabolites may accumulate (see WARNINGS: 134 Renal Effects). 135 Special Populations 136 Pediatric Patients 137 In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels 138 following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND 139 ADMINISTRATION) were found to be similar to those found in normal 140 adults following a 500 mg dose. The terminal half-life appears to be similar in 141 pediatric and adult patients. Pharmacokinetic studies of naproxen were not 142 performed in pediatric patients younger than 5 years of age. Pharmacokinetic 143 parameters appear to be similar following administration of naproxen 144 suspension or tablets in pediatric patients. EC-NAPROSYN has not been 145 studied in subjects under the age of 18. 146 Geriatric Patients 147 Studies indicate that although total plasma concentration of naproxen is 148 unchanged, the unbound plasma fraction of naproxen is increased in the 149 elderly, although the unbound fraction is <1% of the total naproxen 150 concentration. Unbound trough naproxen concentrations in elderly subjects 151 have been reported to range from 0.12% to 0.19% of total naproxen 152 concentration, compared with 0.05% to 0.075% in younger subjects. The 153 clinical significance of this finding is unclear, although it is possible that the 154 increase in free naproxen concentration could be associated with an increase 155 in the rate of adverse events per a given dosage in some elderly patients. 156 Race 157 Pharmacokinetic differences due to race have not been studied. 158 Hepatic Insufficiency 159 Naproxen pharmacokinetics has not been determined in subjects with hepatic 160 insufficiency. 161 Renal Insufficiency 162 Naproxen pharmacokinetics has not been determined in subjects with renal 163 insufficiency. Given that naproxen, its metabolites and conjugates are 164 primarily excreted by the kidney, the potential exists for naproxen metabolites 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 165 to accumulate in the presence of renal insufficiency. Elimination of naproxen 166 is decreased in patients with severe renal impairment. Naproxen-containing 167 products are not recommended for use in patients with moderate to severe and 168 severe renal impairment (creatinine clearance <30 mL/min) (see 169 WARNINGS: Renal Effects). 170 CLINICAL STUDIES 171 General Information 172 Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, 173 juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute 174 gout. Improvement in patients treated for rheumatoid arthritis was 175 demonstrated by a reduction in joint swelling, a reduction in duration of 176 morning stiffness, a reduction in disease activity as assessed by both the 177 investigator and patient, and by increased mobility as demonstrated by a 178 reduction in walking time. Generally, response to naproxen has not been 179 found to be dependent on age, sex, severity or duration of rheumatoid arthritis. 180 In patients with osteoarthritis, the therapeutic action of naproxen has been 181 shown by a reduction in joint pain or tenderness, an increase in range of 182 motion in knee joints, increased mobility as demonstrated by a reduction in 183 walking time, and improvement in capacity to perform activities of daily 184 living impaired by the disease. 185 In a clinical trial comparing standard formulations of naproxen 375 mg bid 186 (750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group 187 terminated prematurely because of adverse events. Nineteen patients in the 188 1500 mg group terminated prematurely because of adverse events. Most of 189 these adverse events were gastrointestinal events. 190 In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and 191 juvenile arthritis, naproxen has been shown to be comparable to aspirin and 192 indomethacin in controlling the aforementioned measures of disease activity, 193 but the frequency and severity of the milder gastrointestinal adverse effects 194 (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, 195 dizziness, lightheadedness) were less in naproxen-treated patients than in 196 those treated with aspirin or indomethacin. 197 In patients with ankylosing spondylitis, naproxen has been shown to decrease 198 night pain, morning stiffness and pain at rest. In double-blind studies the drug 199 was shown to be as effective as aspirin, but with fewer side effects. 200 In patients with acute gout, a favorable response to naproxen was shown by 201 significant clearing of inflammatory changes (eg, decrease in swelling, heat) 202 within 24 to 48 hours, as well as by relief of pain and tenderness. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 203 Naproxen has been studied in patients with mild to moderate pain secondary 204 to postoperative, orthopedic, postpartum episiotomy and uterine contraction 205 pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in 206 patients taking naproxen and within 30 minutes in patients taking naproxen 207 sodium. Analgesic effect was shown by such measures as reduction of pain 208 intensity scores, increase in pain relief scores, decrease in numbers of patients 209 requiring additional analgesic medication, and delay in time to remedication. 210 The analgesic effect has been found to last for up to 12 hours. 211 Naproxen may be used safely in combination with gold salts and/or 212 corticosteroids; however, in controlled clinical trials, when added to the 213 regimen of patients receiving corticosteroids, it did not appear to cause greater 214 improvement over that seen with corticosteroids alone. Whether naproxen has 215 a “steroid-sparing” effect has not been adequately studied. When added to the 216 regimen of patients receiving gold salts, naproxen did result in greater 217 improvement. Its use in combination with salicylates is not recommended 218 because there is evidence that aspirin increases the rate of excretion of 219 naproxen and data are inadequate to demonstrate that naproxen and aspirin 220 produce greater improvement over that achieved with aspirin alone. In 221 addition, as with other NSAIDs, the combination may result in higher 222 frequency of adverse events than demonstrated for either product alone. 223 In 51Cr blood loss and gastroscopy studies with normal volunteers, daily 224 administration of 1000 mg of naproxen as 1000 mg of NAPROSYN 225 (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been 226 demonstrated to cause statistically significantly less gastric bleeding and 227 erosion than 3250 mg of aspirin. 228 Three 6-week, double-blind, multicenter studies with EC-NAPROSYN 229 (naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, 230 n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, 231 including 355 rheumatoid arthritis and osteoarthritis patients who had a recent 232 history of NSAID-related GI symptoms. These studies indicated that EC 233 NAPROSYN and NAPROSYN showed no significant differences in efficacy 234 or safety and had similar prevalence of minor GI complaints. Individual 235 patients, however, may find one formulation preferable to the other. 236 Five hundred and fifty-three patients received EC-NAPROSYN during long 237 term open-label trials (mean length of treatment was 159 days). The rates for 238 clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been 239 historically reported for long-term NSAID use. 240 Geriatric Patients 241 The hepatic and renal tolerability of long-term naproxen administration was 242 studied in two double-blind clinical trials involving 586 patients. Of the 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 243 patients studied, 98 patients were age 65 and older and 10 of the 98 patients 244 were age 75 and older. Naproxen was administered at doses of 375 mg twice 245 daily or 750 mg twice daily for up to 6 months. Transient abnormalities of 246 laboratory tests assessing hepatic and renal function were noted in some 247 patients, although there were no differences noted in the occurrence of 248 abnormal values among different age groups. 249 INDICATIONS AND USAGE 250 Carefully consider the potential benefits and risks of NAPROSYN, EC 251 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and 252 other treatment options before deciding to use NAPROSYN, EC 253 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use 254 the lowest effective dose for the shortest duration consistent with individual 255 patient treatment goals (see WARNINGS). 256 Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 257 NAPROSYN Suspension is indicated: 258 • For the relief of the signs and symptoms of rheumatoid arthritis 259 • For the relief of the signs and symptoms of osteoarthritis 260 • For the relief of the signs and symptoms of ankylosing spondylitis 261 • For the relief of the signs and symptoms of juvenile arthritis 262 Naproxen as NAPROSYN Suspension is recommended for juvenile 263 rheumatoid arthritis in order to obtain the maximum dosage flexibility based 264 on the patient’s weight. 265 Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN 266 Suspension is also indicated: 267 • For relief of the signs and symptoms of tendonitis 268 • For relief of the signs and symptoms of bursitis 269 • For relief of the signs and symptoms of acute gout 270 • For the management of pain 271 • For the management of primary dysmenorrhea 272 EC-NAPROSYN is not recommended for initial treatment of acute pain 273 because the absorption of naproxen is delayed compared to absorption from 274 other naproxen-containing products (see CLINICAL PHARMACOLOGY 275 and DOSAGE AND ADMINISTRATION). 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 276 CONTRAINDICATIONS 277 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 278 NAPROSYN Suspension are contraindicated in patients with known 279 hypersensitivity to naproxen and naproxen sodium. 280 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 281 NAPROSYN Suspension should not be given to patients who have 282 experienced asthma, urticaria, or allergic-type reactions after taking aspirin or 283 other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs 284 have been reported in such patients (see WARNINGS: Anaphylactoid 285 Reactions and PRECAUTIONS: Preexisting Asthma). 286 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 287 NAPROSYN Suspension are contraindicated for the treatment of peri 288 operative pain in the setting of coronary artery bypass graft (CABG) surgery 289 (see WARNINGS). 290 WARNINGS 291 CARDIOVASCULAR EFFECTS 292 Cardiovascular Thrombotic Events 293 Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 294 three years duration have shown an increased risk of serious cardiovascular 295 (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. 296 All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. 297 Patients with known CV disease or risk factors for CV disease may be at 298 greater risk. To minimize the potential risk for an adverse CV event in patients 299 treated with an NSAID, the lowest effective dose should be used for the 300 shortest duration possible. Physicians and patients should remain alert for the 301 development of such events, even in the absence of previous CV symptoms. 302 Patients should be informed about the signs and/or symptoms of serious CV 303 events and the steps to take if they occur. 304 There is no consistent evidence that concurrent use of aspirin mitigates the 305 increased risk of serious CV thrombotic events associated with NSAID use. 306 The concurrent use of aspirin and an NSAID does increase the risk of serious 307 GI events (see Gastrointestinal Effects – Risk of Ulceration, Bleeding, and 308 Perforation). 309 Two large, controlled, clinical trials of a COX-2 selective NSAID for the 310 treatment of pain in the first 10-14 days following CABG surgery found an 311 increased incidence of myocardial infarction and stroke (see 312 CONTRAINDICATIONS). 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 313 Hypertension 314 NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 315 ANAPROX DS and NAPROSYN Suspension, can lead to onset of new 316 hypertension or worsening of pre-existing hypertension, either of which may 317 contribute to the increased incidence of CV events. Patients taking thiazides or 318 loop diuretics may have impaired response to these therapies when taking 319 NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 320 ANAPROX DS and NAPROSYN Suspension, should be used with caution in 321 patients with hypertension. Blood pressure (BP) should be monitored closely 322 during the initiation of NSAID treatment and throughout the course of 323 therapy. 324 Congestive Heart Failure and Edema 325 Fluid retention, edema, and peripheral edema have been observed in some 326 patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX, 327 ANAPROX DS and NAPROSYN Suspension should be used with caution in 328 patients with fluid retention, hypertension, or heart failure. Since each 329 ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium 330 (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of 331 NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of 332 naproxen) of sodium, this should be considered in patients whose overall 333 intake of sodium must be severely restricted. 334 Gastrointestinal Effects – Risk of Ulceration, Bleeding, and 335 Perforation 336 NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 337 ANAPROX DS and NAPROSYN Suspension, can cause serious 338 gastrointestinal (GI) adverse events including inflammation, bleeding, 339 ulceration, and perforation of the stomach, small intestine, or large intestine, 340 which can be fatal. 341 These serious adverse events can occur at any time, with or without warning 342 symptoms, in patients treated with NSAIDs. Only one in five patients, who 343 develop a serious upper GI adverse event on NSAID therapy, is symptomatic. 344 Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in 345 approximately 1% of patients treated for 3-6 months, and in about 2-4% of 346 patients treated for one year. These trends continue with longer duration of 347 use, increasing the likelihood of developing a serious GI event at some time 348 during the course of therapy. However, even short-term therapy is not without 349 risk. The utility of periodic laboratory monitoring has not been demonstrated, 350 nor has it been adequately assessed. Only 1 in 5 patients who develop a 351 serious upper GI adverse event on NSAID therapy is symptomatic. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 352 NSAIDs should be prescribed with extreme caution in those with a prior 353 history of ulcer disease or gastrointestinal bleeding. Patients with a prior 354 history of peptic ulcer disease and/or gastrointestinal bleeding who use 355 NSAIDs have a greater than 10-fold increased risk for developing a GI bleed 356 compared to patients with neither of these risk factors. Other factors that 357 increase the risk for GI bleeding in patients treated with NSAIDs include 358 concomitant use of oral corticosteroids or anticoagulants, longer duration of 359 NSAID therapy, smoking, use of alcohol, older age, and poor general health 360 status. Most spontaneous reports of fatal GI events are in elderly or debilitated 361 patients and therefore, special care should be taken in treating this population. 362 To minimize the potential risk for an adverse GI event in patients treated with 363 an NSAID, the lowest effective dose should be used for the shortest possible 364 duration. Patients and physicians should remain alert for signs and symptoms 365 of GI ulceration and bleeding during NSAID therapy and promptly initiate 366 additional evaluation and treatment if a serious GI adverse event is suspected. 367 This should include discontinuation of the NSAID until a serious GI adverse 368 event is ruled out. For high risk patients, alternate therapies that do not 369 involve NSAIDs should be considered. 370 Epidemiological studies, both of the case-control and cohort design, have 371 demonstrated an association between use of psychotropic drugs that interfere 372 with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. 373 In two studies, concurrent use of an NSAID or aspirin potentiated the risk of 374 bleeding (see PRECAUTIONS: Drug Interactions). Although these studies 375 focused on upper gastrointestinal bleeding, there is reason to believe that 376 bleeding at other sites may be similarly potentiated. 377 NSAIDs should be given with care to patients with a history of inflammatory 378 bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be 379 exacerbated. 380 Renal Effects 381 Long-term administration of NSAIDs has resulted in renal papillary necrosis 382 and other renal injury. Renal toxicity has also been seen in patients in whom 383 renal prostaglandins have a compensatory role in the maintenance of renal 384 perfusion. In these patients, administration of a nonsteroidal 385 anti-inflammatory drug may cause a dose-dependent reduction in 386 prostaglandin formation and, secondarily, in renal blood flow, which may 387 precipitate overt renal decompensation. Patients at greatest risk of this 388 reaction are those with impaired renal function, hypovolemia, heart failure, 389 liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, 390 and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug 391 therapy is usually followed by recovery to the pretreatment state (see 392 WARNINGS: Advanced Renal Disease). 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 393 Advanced Renal Disease 394 No information is available from controlled clinical studies regarding the use 395 of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 396 NAPROSYN Suspension in patients with advanced renal disease. Therefore, 397 treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS 398 and NAPROSYN Suspension is not recommended in these patients with 399 advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX, 400 ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close 401 monitoring of the patient’s renal function is advisable. 402 Anaphylactoid Reactions 403 As with other NSAIDs, anaphylactoid reactions may occur in patients without 404 known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX, 405 ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC 406 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension 407 should not be given to patients with the aspirin triad. This symptom complex 408 typically occurs in asthmatic patients who experience rhinitis with or without 409 nasal polyps, or who exhibit severe, potentially fatal bronchospasm after 410 taking aspirin or other NSAIDs (see CONTRAINDICATIONS and 411 PRECAUTIONS: Preexisting Asthma). Emergency help should be sought 412 in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like 413 anaphylaxis, may have a fatal outcome. 414 Skin Reactions 415 NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 416 ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse 417 events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and 418 toxic epidermal necrolysis (TEN), which can be fatal. These serious events 419 may occur without warning. Patients should be informed about the signs and 420 symptoms of serious skin manifestations and use of the drug should be 421 discontinued at the first appearance of skin rash or any other sign of 422 hypersensitivity. 423 Pregnancy 424 In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, 425 ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided 426 because it may cause premature closure of the ductus arteriosus. 427 PRECAUTIONS 428 General 429 Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, 430 ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, and 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 431 other naproxen products should not be used concomitantly since they all 432 circulate in the plasma as the naproxen anion. 433 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 434 NAPROSYN Suspension cannot be expected to substitute for corticosteroids 435 or to treat corticosteroid insufficiency. Abrupt discontinuation of 436 corticosteroids may lead to disease exacerbation. Patients on prolonged 437 corticosteroid therapy should have their therapy tapered slowly if a decision is 438 made to discontinue corticosteroids and the patient should be observed closely 439 for any evidence of adverse effects, including adrenal insufficiency and 440 exacerbation of symptoms of arthritis. 441 Patients with initial hemoglobin values of 10 g or less who are to receive long 442 term therapy should have hemoglobin values determined periodically. 443 The pharmacological activity of NAPROSYN, EC-NAPROSYN, 444 ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever 445 and inflammation may diminish the utility of these diagnostic signs in 446 detecting complications of presumed noninfectious, noninflammatory painful 447 conditions. 448 Because of adverse eye findings in animal studies with drugs of this class, it is 449 recommended that ophthalmic studies be carried out if any change or 450 disturbance in vision occurs. 451 Hepatic Effects 452 Borderline elevations of one or more liver tests may occur in up to 15% of 453 patients taking NSAIDs including NAPROSYN, EC-NAPROSYN, 454 ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic 455 abnormalities may be the result of hypersensitivity rather than direct toxicity. 456 These laboratory abnormalities may progress, may remain essentially 457 unchanged, or may be transient with continued therapy. The SGPT (ALT) test 458 is probably the most sensitive indicator of liver dysfunction. Notable 459 elevations of ALT or AST (approximately three or more times the upper limit 460 of normal) have been reported in approximately 1% of patients in clinical 461 trials with NSAIDs. In addition, rare cases of severe hepatic reactions, 462 including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic 463 failure, some of them with fatal outcomes have been reported. 464 A patient with symptoms and/or signs suggesting liver dysfunction, or in 465 whom an abnormal liver test has occurred, should be evaluated for evidence 466 of the development of more severe hepatic reaction while on therapy with 467 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 468 NAPROSYN Suspension. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 469 If clinical signs and symptoms consistent with liver disease develop, or if 470 systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC 471 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension 472 should be discontinued. 473 Chronic alcoholic liver disease and probably other diseases with decreased or 474 abnormal plasma proteins (albumin) reduce the total plasma concentration of 475 naproxen, but the plasma concentration of unbound naproxen is increased. 476 Caution is advised when high doses are required and some adjustment of 477 dosage may be required in these patients. It is prudent to use the lowest 478 effective dose. 479 Hematological Effects 480 Anemia is sometimes seen in patients receiving NSAIDs, including 481 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 482 NAPROSYN Suspension. This may be due to fluid retention, occult or gross 483 GI blood loss, or an incompletely described effect upon erythropoiesis. 484 Patients on long-term treatment with NSAIDs, including NAPROSYN, EC 485 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, 486 should have their hemoglobin or hematocrit checked if they exhibit any signs 487 or symptoms of anemia. 488 NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding 489 time in some patients. Unlike aspirin, their effect on platelet function is 490 quantitatively less, of shorter duration, and reversible. Patients receiving either 491 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 492 NAPROSYN Suspension who may be adversely affected by alterations in 493 platelet function, such as those with coagulation disorders or patients 494 receiving anticoagulants, should be carefully monitored. 495 Preexisting Asthma 496 Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in 497 patients with aspirin-sensitive asthma has been associated with severe 498 bronchospasm, which can be fatal. Since cross reactivity, including 499 bronchospasm, between aspirin and other nonsteroidal anti-inflammatory 500 drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC 501 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension 502 should not be administered to patients with this form of aspirin sensitivity and 503 should be used with caution in patients with preexisting asthma. 504 Information for Patients 505 Patients should be informed of the following information before initiating 506 therapy with an NSAID and periodically during the course of ongoing 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 507 therapy. Patients should also be encouraged to read the NSAID 508 Medication Guide that accompanies each prescription dispensed. 509 1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 510 NAPROSYN Suspension, like other NSAIDs, may cause serious CV side 511 effects, such as MI or stroke, which may result in hospitalization and even 512 death. Although serious CV events can occur without warning symptoms, 513 patients should be alert for the signs and symptoms of chest pain, 514 shortness of breath, weakness, slurring of speech, and should ask for 515 medical advice when observing any indicative sign or symptoms. Patients 516 should be apprised of the importance of this follow-up (see WARNINGS: 517 Cardiovascular Effects). 518 2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 519 NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort 520 and, rarely, serious GI side effects, such as ulcers and bleeding, which 521 may result in hospitalization and even death. Although serious GI tract 522 ulcerations and bleeding can occur without warning symptoms, patients 523 should be alert for the signs and symptoms of ulcerations and bleeding, 524 and should ask for medical advice when observing any indicative sign or 525 symptoms including epigastric pain, dyspepsia, melena, and hematemesis. 526 Patients should be apprised of the importance of this follow-up (see 527 WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, 528 and Perforation). 529 3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 530 NAPROSYN Suspension, like other NSAIDs, can cause serious skin side 531 effects such as exfoliative dermatitis, SJS, and TEN, which may result in 532 hospitalizations and even death. Although serious skin reactions may 533 occur without warning, patients should be alert for the signs and 534 symptoms of skin rash and blisters, fever, or other signs of 535 hypersensitivity such as itching, and should ask for medical advice when 536 observing any indicative signs or symptoms. Patients should be advised to 537 stop the drug immediately if they develop any type of rash and contact 538 their physicians as soon as possible. 539 4. Patients should promptly report signs or symptoms of unexplained weight 540 gain or edema to their physicians. 541 5. Patients should be informed of the warning signs and symptoms of 542 hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper 543 quadrant tenderness, and “flu-like” symptoms). If these occur, patients 544 should be instructed to stop therapy and seek immediate medical therapy. 545 6. Patients should be informed of the signs of an anaphylactoid reaction (eg, 546 difficulty breathing, swelling of the face or throat). If these occur, patients 547 should be instructed to seek immediate emergency help (see 548 WARNINGS). 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 549 7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, 550 ANAPROX, ANAPROX DS and NAPROSYN Suspension should be 551 avoided because it may cause premature closure of the ductus arteriosus. 552 8. Caution should be exercised by patients whose activities require alertness 553 if they experience drowsiness, dizziness, vertigo or depression during 554 therapy with naproxen. 555 Laboratory Tests 556 Because serious GI tract ulcerations and bleeding can occur without warning 557 symptoms, physicians should monitor for signs or symptoms of GI bleeding. 558 Patients on long-term treatment with NSAIDs should have their CBC and a 559 chemistry profile checked periodically. If clinical signs and symptoms 560 consistent with liver or renal disease develop, systemic manifestations occur 561 (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, 562 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 563 NAPROSYN Suspension should be discontinued. 564 Drug Interactions 565 ACE-inhibitors 566 Reports suggest that NSAIDs may diminish the antihypertensive effect of 567 ACE-inhibitors. This interaction should be given consideration in patients 568 taking NSAIDs concomitantly with ACE-inhibitors. 569 Antacids and Sucralfate 570 Concomitant administration of some antacids (magnesium oxide or aluminum 571 hydroxide) and sucralfate can delay the absorption of naproxen. 572 Aspirin 573 When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX 574 DS or NAPROSYN Suspension is administered with aspirin, its protein 575 binding is reduced, although the clearance of free NAPROSYN, EC 576 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is 577 not altered. The clinical significance of this interaction is not known; 578 however, as with other NSAIDs, concomitant administration of naproxen and 579 naproxen sodium and aspirin is not generally recommended because of the 580 potential of increased adverse effects. 581 Cholestyramine 582 As with other NSAIDs, concomitant administration of cholestyramine can 583 delay the absorption of naproxen. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 584 Diuretics 585 Clinical studies, as well as postmarketing observations, have shown that 586 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 587 NAPROSYN Suspension can reduce the natriuretic effect of furosemide and 588 thiazides in some patients. This response has been attributed to inhibition of 589 renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the 590 patient should be observed closely for signs of renal failure (see 591 WARNINGS: Renal Effects), as well as to assure diuretic efficacy. 592 Lithium 593 NSAIDs have produced an elevation of plasma lithium levels and a reduction 594 in renal lithium clearance. The mean minimum lithium concentration 595 increased 15% and the renal clearance was decreased by approximately 20%. 596 These effects have been attributed to inhibition of renal prostaglandin 597 synthesis by the NSAID. Thus, when NSAIDs and lithium are administered 598 concurrently, subjects should be observed carefully for signs of lithium 599 toxicity. 600 Methotrexate 601 NSAIDs have been reported to competitively inhibit methotrexate 602 accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other 603 nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular 604 secretion of methotrexate in an animal model. This may indicate that they 605 could enhance the toxicity of methotrexate. Caution should be used when 606 NSAIDs are administered concomitantly with methotrexate. 607 Warfarin 608 The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that 609 users of both drugs together have a risk of serious GI bleeding higher than 610 users of either drug alone. No significant interactions have been observed in 611 clinical studies with naproxen and coumarin-type anticoagulants. However, 612 caution is advised since interactions have been seen with other nonsteroidal 613 agents of this class. The free fraction of warfarin may increase substantially in 614 some subjects and naproxen interferes with platelet function. 615 Selective Serotonin Reuptake Inhibitors (SSRIs) 616 There is an increased risk of gastrointestinal bleeding when selective serotonin 617 reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be 618 used when NSAIDs are administered concomitantly with SSRIs. 619 Other Information Concerning Drug Interactions 620 Naproxen is highly bound to plasma albumin; it thus has a theoretical 621 potential for interaction with other albumin-bound drugs such as coumarin 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 622 type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. 623 Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or 624 sulphonylurea should be observed for adjustment of dose if required. 625 Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the 626 antihypertensive effect of propranolol and other beta-blockers. 627 Probenecid given concurrently increases naproxen anion plasma levels and 628 extends its plasma half-life significantly. 629 Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive 630 antacid therapy, concomitant administration of EC-NAPROSYN is not 631 recommended. 632 Drug/Laboratory Test Interaction 633 Naproxen may decrease platelet aggregation and prolong bleeding time. This 634 effect should be kept in mind when bleeding times are determined. 635 The administration of naproxen may result in increased urinary values for 17 636 ketogenic steroids because of an interaction between the drug and/or its 637 metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy 638 corticosteroid measurements (Porter-Silber test) do not appear to be 639 artifactually altered, it is suggested that therapy with naproxen be temporarily 640 discontinued 72 hours before adrenal function tests are performed if the 641 Porter-Silber test is to be used. 642 Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic 643 acid (5HIAA). 644 Carcinogenesis 645 A 2-year study was performed in rats to evaluate the carcinogenic potential of 646 naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). 647 The maximum dose used was 0.28 times the systemic exposure to humans at 648 the recommended dose. No evidence of tumorigenicity was found. 649 Pregnancy 650 Teratogenic Effects 651 Pregnancy Category C 652 Reproduction studies have been performed in rats at 20 mg/kg/day 653 (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 654 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and 655 mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic 656 exposure) with no evidence of impaired fertility or harm to the fetus due to the 657 drug. However, animal reproduction studies are not always predictive of 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 658 human response. There are no adequate and well-controlled studies in 659 pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX 660 DS and NAPROSYN Suspension should be used in pregnancy only if the 661 potential benefit justifies the potential risk to the fetus. 662 Nonteratogenic Effects 663 There is some evidence to suggest that when inhibitors of prostaglandin 664 synthesis are used to delay preterm labor there is an increased risk of neonatal 665 complications such as necrotizing enterocolitis, patent ductus arteriosus and 666 intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay 667 parturition has been associated with persistent pulmonary hypertension, renal 668 dysfunction and abnormal prostaglandin E levels in preterm infants. Because 669 of the known effects of nonsteroidal anti-inflammatory drugs on the fetal 670 cardiovascular system (closure of ductus arteriosus), use during pregnancy 671 (particularly late pregnancy) should be avoided. 672 Labor and Delivery 673 In rat studies with NSAIDs, as with other drugs known to inhibit 674 prostaglandin synthesis, an increased incidence of dystocia, delayed 675 parturition, and decreased pup survival occurred. Naproxen-containing 676 products are not recommended in labor and delivery because, through its 677 prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal 678 circulation and inhibit uterine contractions, thus increasing the risk of uterine 679 hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX, 680 ANAPROX DS and NAPROSYN Suspension on labor and delivery in 681 pregnant women are unknown. 682 Nursing Mothers 683 The naproxen anion has been found in the milk of lactating women at a 684 concentration equivalent to approximately 1% of maximum naproxen 685 concentration in plasma. Because of the possible adverse effects of 686 prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be 687 avoided. 688 Pediatric Use 689 Safety and effectiveness in pediatric patients below the age of 2 years have 690 not been established. Pediatric dosing recommendations for juvenile arthritis 691 are based on well-controlled studies (see DOSAGE AND 692 ADMINISTRATION). There are no adequate effectiveness or dose-response 693 data for other pediatric conditions, but the experience in juvenile arthritis and 694 other use experience have established that single doses of 2.5 to 5 mg/kg (as 695 naproxen suspension, see DOSAGE AND ADMINISTRATION), with total 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 696 daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients 697 over 2 years of age. 698 Geriatric Use 699 Studies indicate that although total plasma concentration of naproxen is 700 unchanged, the unbound plasma fraction of naproxen is increased in the 701 elderly. Caution is advised when high doses are required and some adjustment 702 of dosage may be required in elderly patients. As with other drugs used in the 703 elderly, it is prudent to use the lowest effective dose. 704 Experience indicates that geriatric patients may be particularly sensitive to 705 certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or 706 debilitated patients seem to tolerate peptic ulceration or bleeding less well 707 when these events do occur. Most spontaneous reports of fatal GI events are in 708 the geriatric population (see WARNINGS). 709 Naproxen is known to be substantially excreted by the kidney, and the risk of 710 toxic reactions to this drug may be greater in patients with impaired renal 711 function. Because elderly patients are more likely to have decreased renal 712 function, care should be taken in dose selection, and it may be useful to 713 monitor renal function. Geriatric patients may be at a greater risk for the 714 development of a form of renal toxicity precipitated by reduced prostaglandin 715 formation during administration of nonsteroidal anti-inflammatory drugs (see 716 WARNINGS: Renal Effects). 717 ADVERSE REACTIONS 718 Adverse reactions reported in controlled clinical trials in 960 patients treated 719 for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions 720 in patients treated chronically were reported 2 to 10 times more frequently 721 than they were in short-term studies in the 962 patients treated for mild to 722 moderate pain or for dysmenorrhea. The most frequent complaints reported 723 related to the gastrointestinal tract. 724 A clinical study found gastrointestinal reactions to be more frequent and more 725 severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen 726 compared to those taking 750 mg naproxen (see CLINICAL 727 PHARMACOLOGY). 728 In controlled clinical trials with about 80 pediatric patients and in well 729 monitored, open-label studies with about 400 pediatric patients with juvenile 730 arthritis treated with naproxen, the incidence of rash and prolonged bleeding 731 times were increased, the incidence of gastrointestinal and central nervous 732 system reactions were about the same, and the incidence of other reactions 733 were lower in pediatric patients than in adults. 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 734 In patients taking naproxen in clinical trials, the most frequently reported 735 adverse experiences in approximately 1% to 10% of patients are: 736 Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, 737 nausea, constipation, diarrhea, dyspepsia, stomatitis 738 Central Nervous System: headache, dizziness, drowsiness, 739 lightheadedness, vertigo 740 Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, 741 purpura 742 Special Senses: tinnitus, visual disturbances, hearing disturbances 743 Cardiovascular: edema, palpitations 744 General: dyspnea, thirst 745 Incidence of reported reaction between 3% and 9%. Those reactions 746 occurring in less than 3% of the patients are unmarked. 747 In patients taking NSAIDs, the following adverse experiences have also been 748 reported in approximately 1% to 10% of patients. 749 Gastrointestinal (GI) Experiences, including: flatulence, gross 750 bleeding/perforation, GI ulcers (gastric/duodenal), vomiting 751 General: abnormal renal function, anemia, elevated liver enzymes, increased 752 bleeding time, rashes 753 The following are additional adverse experiences reported in <1% of patients 754 taking naproxen during clinical trials and through postmarketing reports. 755 Those adverse reactions observed through postmarketing reports are italicized. 756 Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual 757 disorders, pyrexia (chills and fever) 758 Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary 759 edema 760 Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, 761 pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease 762 (ulcerative colitis, Crohn’s disease), nonpeptic gastrointestinal ulceration, 763 ulcerative stomatitis, esophagitis, peptic ulceration 764 Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases 765 have been fatal) 766 Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, 767 agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 768 Metabolic and Nutritional: hyperglycemia, hypoglycemia 769 Nervous System: inability to concentrate, depression, dream abnormalities, 770 insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive 771 dysfunction, convulsions 772 Respiratory: eosinophilic pneumonitis, asthma 773 Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, 774 erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, 775 pustular reaction, systemic lupus erythematoses, bullous reactions, including 776 Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity 777 reactions, including rare cases resembling porphyria cutanea tarda 778 (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or 779 other symptoms suggestive of pseudoporphyria occur, treatment should be 780 discontinued and the patient monitored. 781 Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar 782 optic neuritis, papilledema 783 Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial 784 nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary 785 necrosis, raised serum creatinine 786 Reproduction (female): infertility 787 In patients taking NSAIDs, the following adverse experiences have also been 788 reported in <1% of patients. 789 Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite 790 changes, death 791 Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, 792 hypotension, myocardial infarction 793 Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, 794 glossitis, eructation 795 Hepatobiliary: hepatitis, liver failure 796 Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia 797 Metabolic and Nutritional: weight changes 798 Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, 799 somnolence, tremors, convulsions, coma, hallucinations 800 Respiratory: asthma, respiratory depression, pneumonia 801 Dermatologic: exfoliative dermatitis 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 802 Special Senses: blurred vision, conjunctivitis 803 Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria 804 OVERDOSAGE 805 Symptoms and Signs 806 Significant naproxen overdosage may be characterized by lethargy, dizziness, 807 drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, 808 nausea, transient alterations in liver function, hypoprothrombinemia, renal 809 dysfunction, metabolic acidosis, apnea, disorientation or vomiting. 810 Gastrointestinal bleeding can occur. Hypertension, acute renal failure, 811 respiratory depression, and coma may occur, but are rare. Anaphylactoid 812 reactions have been reported with therapeutic ingestion of NSAIDs, and may 813 occur following an overdose. Because naproxen sodium may be rapidly 814 absorbed, high and early blood levels should be anticipated. A few patients 815 have experienced convulsions, but it is not clear whether or not these were 816 drug-related. It is not known what dose of the drug would be life threatening. 817 The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 818 mg/kg in hamsters, and greater than 1000 mg/kg in dogs. 819 Treatment 820 Patients should be managed by symptomatic and supportive care following a 821 NSAID overdose. There are no specific antidotes. Hemodialysis does not 822 decrease the plasma concentration of naproxen because of the high degree of 823 its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 824 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients 825 seen within 4 hours of ingestion with symptoms or following a large overdose. 826 Forced diuresis, alkalinization of urine or hemoperfusion may not be useful 827 due to high protein binding. 828 DOSAGE AND ADMINISTRATION 829 Carefully consider the potential benefits and risks of NAPROSYN, EC 830 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and 831 other treatment options before deciding to use NAPROSYN, EC 832 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. 833 Use the lowest effective dose for the shortest duration consistent with 834 individual patient treatment goals (see WARNINGS). 835 After observing the response to initial therapy with NAPROSYN, EC 836 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the 837 dose and frequency should be adjusted to suit an individual patient’s needs. 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 838 Different dose strengths and formulations (ie, tablets, suspension) of the 839 drug are not necessarily bioequivalent. This difference should be taken 840 into consideration when changing formulation. 841 Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, 842 ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they 843 have pharmacokinetic differences that may affect onset of action. Onset of 844 pain relief can begin within 30 minutes in patients taking naproxen sodium 845 and within 1 hour in patients taking naproxen. Because EC-NAPROSYN 846 dissolves in the small intestine rather than in the stomach, the absorption of 847 the drug is delayed compared to the other naproxen formulations (see 848 CLINICAL PHARMACOLOGY). 849 The recommended strategy for initiating therapy is to choose a formulation 850 and a starting dose likely to be effective for the patient and then adjust the 851 dosage based on observation of benefit and/or adverse events. A lower dose 852 should be considered in patients with renal or hepatic impairment or in elderly 853 patients (see WARNINGS and PRECAUTIONS). 854 Geriatric Patients 855 Studies indicate that although total plasma concentration of naproxen is 856 unchanged, the unbound plasma fraction of naproxen is increased in the 857 elderly. Caution is advised when high doses are required and some adjustment 858 of dosage may be required in elderly patients. As with other drugs used in the 859 elderly, it is prudent to use the lowest effective dose. 860 Patients With Moderate to Severe Renal Impairment 861 Naproxen-containing products are not recommended for use in patients with 862 moderate to severe and severe renal impairment (creatinine clearance <30 863 mL/min) (see WARNINGS: Renal Effects). 864 Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis NAPROSYN 250 mg or 375 mg or 500 mg twice daily twice daily twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp) or 375 mg (15 mL/3 tsp) or 500 mg (20 mL/4 tsp) twice daily twice daily twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 865 To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet 866 should not be broken, crushed or chewed during ingestion. NAPROSYN 867 Suspension should be shaken gently before use. 868 During long-term administration, the dose of naproxen may be adjusted up or 869 down depending on the clinical response of the patient. A lower daily dose 870 may suffice for long-term administration. The morning and evening doses do 871 not have to be equal in size and the administration of the drug more frequently 872 than twice daily is not necessary. 873 In patients who tolerate lower doses well, the dose may be increased to 874 naproxen 1500 mg/day for limited periods of up to 6 months when a higher 875 level of anti-inflammatory/analgesic activity is required. When treating such 876 patients with naproxen 1500 mg/day, the physician should observe sufficient 877 increased clinical benefits to offset the potential increased risk. The morning 878 and evening doses do not have to be equal in size and administration of the 879 drug more frequently than twice daily does not generally make a difference in 880 response (see CLINICAL PHARMACOLOGY). 881 Juvenile Arthritis 882 The use of NAPROSYN Suspension is recommended for juvenile arthritis in 883 children 2 years or older because it allows for more flexible dose titration 884 based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day 885 produced plasma levels of naproxen similar to those seen in adults taking 500 886 mg of naproxen (see CLINICAL PHARMACOLOGY). 887 The recommended total daily dose of naproxen is approximately 10 mg/kg 888 given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup 889 marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the 890 NAPROSYN Suspension. The following table may be used as a guide for 891 dosing of NAPROSYN Suspension: 892 Patient’s Weight Dose Administered as 893 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 894 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 895 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily 896 Management of Pain, Primary Dysmenorrhea, and Acute 897 Tendonitis and Bursitis 898 The recommended starting dose is 550 mg of naproxen sodium as 899 ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg 900 every 6 to 8 hours as required. The initial total daily dose should not exceed 901 1375 mg of naproxen sodium. Thereafter, the total daily dose should not 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 902 exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is 903 more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the 904 management of acute painful conditions when prompt onset of pain relief is 905 desired. NAPROSYN may also be used but EC-NAPROSYN is not 906 recommended for initial treatment of acute pain because absorption of 907 naproxen is delayed compared to other naproxen-containing products (see 908 CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). 909 Acute Gout 910 The recommended starting dose is 750 mg of NAPROSYN followed by 250 911 mg every 8 hours until the attack has subsided. ANAPROX may also be used 912 at a starting dose of 825 mg followed by 275 mg every 8 hours. EC 913 NAPROSYN is not recommended because of the delay in absorption (see 914 CLINICAL PHARMACOLOGY). 915 HOW SUPPLIED 916 NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR 917 LE 250 on one side and scored on the other. Packaged in light-resistant bottles 918 of 100. 919 100’s (bottle): NDC 0004-6313-01. 920 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. 921 Packaged in light-resistant bottles of 100. 922 100’s (bottle): NDC 0004-6314-01. 923 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and 924 scored on the other. Packaged in light-resistant bottles of 100. 925 100’s (bottle): NDC 0004-6316-01. 926 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light 927 resistant containers. 928 NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 929 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 930 0004-0028-28). 931 Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). 932 Dispense in light-resistant containers. Shake gently before use. 933 EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex 934 coated tablets imprinted with NPR EC 375 on one side. Packaged in light 935 resistant bottles of 100. 936 100’s (bottle): NDC 0004-6415-01. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 937 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. 938 Packaged in light-resistant bottles of 100. 939 100’s (bottle): NDC 0004-6416-01. 940 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light 941 resistant containers. 942 ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, 943 engraved with NPS-275 on one side. Packaged in bottles of 100. 944 100’s (bottle): NDC 0004-6202-01. 945 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 946 ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong 947 shaped, engraved with NPS 550 on one side and scored on both sides. 948 Packaged in bottles of 100. 949 100’s (bottle): NDC 0004-6203-01. 950 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 951 Revised: September 2007 952 953 Medication Guide 954 for 955 Non-steroidal Anti-Inflammatory Drugs (NSAIDs) 956 (See the end of this Medication Guide for a list of prescription NSAID 957 medicines.) 958 959 What is the most important information I should know about medicines 960 called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? 961 NSAID medicines may increase the chance of a heart attack or 962 stroke that can lead to death. This chance increases: 963 • with longer use of NSAID medicines 964 • in people who have heart disease 965 966 NSAID medicines should never be used right before or after a 967 heart surgery called a “coronary artery bypass graft (CABG).” 968 NSAID medicines can cause ulcers and bleeding in the stomach 969 and intestines at any time during treatment. Ulcers and bleeding: 970 • can happen without warning symptoms 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 971 • may cause death 972 973 The chance of a person getting an ulcer or bleeding increases 974 with: 975 • taking medicines called “corticosteroids” and 976 “anticoagulants” 977 • longer use 978 • smoking 979 • drinking alcohol 980 • older age 981 • having poor health 982 983 NSAID medicines should only be used: 984 • exactly as prescribed 985 • at the lowest dose possible for your treatment 986 • for the shortest time needed 987 988 What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? 989 NSAID medicines are used to treat pain and redness, swelling, and heat 990 (inflammation) from medical conditions such as: 991 • different types of arthritis 992 • menstrual cramps and other types of short-term pain 993 994 Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? 995 Do not take an NSAID medicine: 996 • if you had an asthma attack, hives, or other allergic reaction with 997 aspirin or any other NSAID medicine 998 • for pain right before or after heart bypass surgery 999 1000 Tell your healthcare provider: 1001 • about all of your medical conditions. 1002 • about all of the medicines you take. NSAIDs and some other 1003 medicines can interact with each other and cause serious side 1004 effects. Keep a list of your medicines to show to your 1005 healthcare provider and pharmacist. 1006 • if you are pregnant. NSAID medicines should not be used by 1007 pregnant women late in their pregnancy. 1008 • if you are breastfeeding. Talk to your doctor. 1009 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 1010 What are the possible side effects of Non-Steroidal Anti-Inflammatory 1011 Drugs (NSAIDs)? Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness 1012 1013 Get emergency help right away if you have any of the following 1014 symptoms: • shortness of breath or trouble • slurred speech breathing • swelling of the face or • chest pain throat • weakness in one part or side of your body 1015 1016 Stop your NSAID medicine and call your healthcare provider right away 1017 if you have any of the following symptoms: • nausea • there is blood in your • more tired or weaker than usual bowel movement or it is • itching black and sticky like tar • your skin or eyes look yellow • unusual weight gain • stomach pain • skin rash or blisters with • flu-like symptoms fever • vomit blood • swelling of the arms and legs, hands and feet 1018 1019 These are not all the side effects with NSAID medicines. Talk to your 1020 healthcare provider or pharmacist for more information about NSAID 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 1021 medicines. Call your doctor for medical advice about side effects. You may 1022 report side effects to FDA at 1-800-FDA-1088 or Roche at 1-800-526-6367. 1023 Other information about Non-Steroidal Anti-Inflammatory Drugs 1024 (NSAIDs): 1025 • Aspirin is an NSAID medicine but it does not increase the chance of a 1026 heart attack. Aspirin can cause bleeding in the brain, stomach, and 1027 intestines. Aspirin can also cause ulcers in the stomach and intestines. 1028 • Some of these NSAID medicines are sold in lower doses without a 1029 prescription (over-the-counter). Talk to your healthcare provider before 1030 using over-the-counter NSAIDs for more than 10 days. 1031 1032 NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex® Diclofenac Cataflam®, Voltaren®, Arthrotec™ (combined with misoprostol) Diflunisal Dolobid® Etodolac Lodine®, Lodine®XL Fenoprofen Nalfon®, Nalfon®200 Flurbirofen Ansaid® Ibuprofen Motrin®, Tab-Profen®, Vicoprofen® (combined with hydrocodone), Combunox™ (combined with oxycodone) Indomethacin Indocin®, Indocin®SR, Indo-Lemmon™, Indomethagan™ Ketoprofen Oruvail® Ketorolac Toradol® Mefenamic Acid Ponstel® Meloxicam Mobic® Nabumetone Relafen® Naproxen Naprosyn®, Anaprox®, Anaprox®DS, EC-Naprosyn® , Naprelan®, Naprapac® (copackaged with lansoprazole) Oxaprozin Daypro® Piroxicam Feldene® Sulindac Clinoril® Tolmetin Tolectin®, Tolectin DS®, Tolectin®600 1033 *Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) 1034 NSAID, and is usually used for less than 10 days to treat pain. The OTC 1035 NSAID label warns that long term continuous use may increase the risk of 1036 heart attack or stroke. 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 1037 This Medication Guide has been approved by the U.S. Food and Drug 1038 Administration. 1039 Medication Guide Revised: Month Year 1040 1041 All registered trademarks in this document are the property of their respective 1042 owners. 1043 Distributed by: Logo & Address 1045 1046 1047 XXXXXXXX 1048 Copyright © 1999-200X by Roche Laboratories Inc. All rights reserved. 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:08.990980	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017581s110,18164s60,18965s18,20067s17lbl.pdf', 'application_number': 18965, 'submission_type': 'SUPPL ', 'submission_number': 18}
11,388	(RoChe) EC-NAPROSYN~ (naproxen delayed-release tablets) NAPROSYN~ (naproxen tablets) ANAPROX~/ANAPROX~ DS (naproxen sodium tablets) NAPROSYN~ (naproxen suspension) Rx only Cardiovascular Risk . NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fataL. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). . Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CAB G) surgery (see WARNINGS). Gastrointestinal Risk . NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fataL. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). DESCRIPTION Naproxen is a proprionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-a- methyl-2-naphthaleneacetic acid and (S)-6-methoxy-a-methyl-2- naphthaJeneacetic acid, sodium salt, respectively. Naproxen and naproxen sodium have the following stiyctures, respectively: ;Oo R..." napro'en (R..COOH) C14HI.o, mol wi 230.26 CH;¡ napro,.n ,odium (R.-COONa) C14H "NaO, mol wl 252.23 CH:iÜ Naproxen has a molecular weight of 230.26 and a molecular formula of C14H1403. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of CI4H13Na03. Naproxen is an odorless, white to off-white crystallne substance. It is lipid- soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coeffcient of naproxen at pH 7.4 is 1.6 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of naproxen, pink tablets containing 375 mg of naproxen and yellow tablets containing 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, iron oxides, povidone and magnesium . stearate. EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric- coated :white tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified water. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH4. ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg ofnaproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue tablets containing 550 mg of naproxen sodium for oral administration. The inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Opadry YS-1-4216. NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle containing, sucrose, magnesium aluminum silcate, sorbitol solution and sodium chloride (30 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C Yellow No.6, imitation pineapple flavor, imitation orange flavor and purified water. The pH ofthe suspension ranges from 2.2 to 3.7. CLINICAL PHARMACOLOGY Pharmacodynamics Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) Pharmacokinetics Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels ofnaproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. Absorption Immediate Release After administration of NAPROSYN tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN Suspension arc attained in 1 to 4 hours. Delayed Release EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC- NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radio labeled EC-NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (T max) were observed, but there were no differences in total absorption as measured by Cmax and AUC: 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) EC-NAPROSYN* NAPROSYN* 500 mg bid 500 mg bid Cmax (f.g/mL) 94.9 (18%) 97.4 (13%) Tmax (hours) 4 (39%) 1.9 (61 %) AUCo-12 hr (f.g'hr/mL) 845 (20%) 767 (15%) Mean value (coefficient of variation) Antacid Effects When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly. Food Effects When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (T max), but did not affect peak naproxen levels (Cmax). Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS: Nursing Mothers). Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acyl glucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (":1 %), 6-0-desmethyl naproxen (":1 %) or their conjugates (66% to 92%). The plasma 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPRO~/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen's metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate (see WARNINGS: Renal Effects). Special Populations Pediatric Patients In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose ofnaproxen suspension (see DOSAGE AND ADMINISTRATION) were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not pcrformed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN has not been studied in subjects under the age of 18. Geriatric Patients Studies indicate that although total plasma concentration of nàproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is ..1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Race Pharmacokinetic differences due to race have not been studied. Hepatic Insufficiency Naproxen pharmacokinetics has not been determined in subjects with hepatic insuffciency. Renal Insufficiency Naproxen pharmacokinetics has not been determined in subjects with renal insuffciency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance ..30 mL/min) (see WARNINGS: Renal Effects). CLINICAL STUDIES General Information Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swellng, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadcdness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studics the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (eg, decrease in swellng, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxcn has a "steroid-sparing" effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alonc. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These studies indicated that EC- NAPROSYN and NAPROSYN showed no significant differences in effcacy or safety and had similar prevalence of minor GI complaints. Individual patients, however, may find one formulation preferable to the other. Five hundred and fifty-three patients received EC-NAPROSYN during long- term open-label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use. Geriatric Patients The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. INDICATIONS AND USAGE Carcfully consider the potential benefits and risks of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is indicated: . For the relief of the signs and symptoms of rheumatoid arthritis . For the relief ofthe signs and symptoms of osteoarthritis . For the relief of the signs and symptoms of ankylosing spondylitis . For the relief of the signs and symptoms of juvenile arthritis Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the patient's weight. Naproxen as NAPROSYN~ ANAPROX, ANAPROX DS and NAPROSYN Suspension is also indicated: . For relief of the signs and symptoms of tendonitis . For relief of the signs and symptoms of bursitis . For relief of the signs and symptoms of acute gout . For the management of pain . For the management of primary dysmenorrhea EC-NAPROSYN is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) CONTRAINDICA TIONS NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated in patients with known hypersensitivity to naproxen and naproxen sodium. NAPROSYN, EC-NAPROSYN,' ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma). NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated for the treatment of peri- operative pain in the setting of coronary artery bypass graft (CAB G) surgery (see WARNINGS). WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fataL. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigatcs the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. (see CONTRAINDICA TIONS). 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) Hypertension NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazid~s or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used with caution in patients with fluid retention, hypertension, or hear failure. Since each ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of naproxen) of sodium, this should be considered in patients whose overall intakc of sodium must be severely restricted. Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause seflOUS gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fataL. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs OCCU! in approximately 1 % of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an NSAID or aspirin potcntiated the risk of bleeding (see PRECAUTIONS - Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to belicve that bleeding at other sites may be similarly potentiated. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated. Renal Effects Long-term administration of NSAIDs has resulted in renal papilary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followcd by recovery to the pretreatment state (see WARNINGS: Advanced Renal Disease). 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Advanced Renal Disease No information is available from controlled clinical studies regarding the use of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension in patients with advanced renal disease. Therefore, treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is not recommended in these patients with advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Skin Reactions NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fataL. These serious events may occur without warning. Patients should be inforied about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus areriosus. PRECAUTIONS General Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE~, and 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspcnsion cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. Patients with initial hemoglobin values of 109 or less who are to receive long- term therapy should have hemoglobin values determined periodically. The pharmacological activity of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (AL T) test is probably the most sensitive indicator of liver dysfunction. Notable elevations of AL T or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1 % of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with .symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSY~ (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension should be discontinued. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustmcnt of dosage may be required in these patients. It is prudent to use the lowest effective dose. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet fuction is quantitatively less, of shorter duration, and reversible. Patients receiving either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension who may be adversely affected by alterations in platelct function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fataL. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), N.APROSYN (naproxen suspension) therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, may causc serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when obsei:ving any indicative sign or symptoms. Patients should be apprised ofthe importance of this follow-up (see WARNINGS: Cardiovascular Effects). 2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other ;N"SAIDs, can cause GI discomfort and, rarely, serious GI side cffccts, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised ofthe importance of this follow-up (see WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation). 3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (eg, diffculty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek in'mediate emergency help (see WARNINGS). 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) 7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. 8. Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profie checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspcnsion should be discontinued. Drug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Antacids and Sucralfate Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Aspirin When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is administered with aspirin, its protein binding is reduced, although the clearance of free NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of naproxen and naproxen sodium and aspirin is not generally recommended because of the potential of increased adverse effects. Ch o/es tyramine As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Diuretics Clinical studies, as well as postmarketing observations, have shown that NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the rcnal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other nonsteroidal anti-inflammatory drugs have been rcported to reduce the tubular secretion of methotrexate in an animal modeL. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. No significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants. However, caution is advised since interactions have been seen with other nonsteroidal agents of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function. Selective Serotonin Reuptake Inhibitors (SSRls) There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administed concomintantly with SSRIs. Other Information Concerning Drug Interactions Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin- 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) type anticoagulants, sulphonylureas, hydantoins, othcr NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of EC-NAPROSYN is not recommended. Drug/Laboratory Test Interaction Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. The administration of naproxen may result in increased urinary values for 17- ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy- corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). The maximum dose used was 0.28 times the, systemic exposure to humans at the recommended dose. No evidence oftumorigenicity was found. Pregnancy Teratogenic Effects Pregnancy Category C Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. However, animal reproduction studies are not always predictive of 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) human response. There are no adequate and well-controlled studies in pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects There is some evidence to suggest that when inhibitors of prostaglandin synthesis are us cd to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (paricularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may advcrsely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension on labor and delivery in pregnant women are unknown. Nursing Mothers The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1 % of maximum naproxen concentration in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided. Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE- AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND ADMINISTRATION), with total 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. Geriatric Use Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric paticnts may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS). Naproxen 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 fuction, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs (see WARNINGS: Renal Effects). ADVERSE REACTIONS Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen (see CLINICAL PHARMACOLOGY). In controlled clinical trials with about 80 pediatric patients and in well- monitored, open-label studies with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1 % to 10% of patients are: Gastrointestinal (GI) Experiences, including: heartburn , abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis Central Nervous System: headache , dizziness * , drowsiness * , lightheadedness, vertigo Dermatologic: pruritus (itching) * , skin eruptions * , ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: edema, palpitations General: dyspnea, thirst Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1 % to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in ..1 % of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chils andfever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease), nonpeptic gastrointestinal ulceration, ulcerative stomatitis, esophagitis, peptic ulceration Hepatobilary: jaundice, abnormal liver function tests, hepatits (some cases have been fatal) Hemic and Lymphatic: eosinophila, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilc pneumonits, asthma Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, . erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitve dermatitis, photosensitvity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragilty, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored Special Senses: hearing impairment, corneal opacity, papilitis, retrobulbar optic neuritis, papiledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papilary necrosis, raised serum creatinine Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in":l % of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulccrs, gastritis, glossitis, eructation syncope, arrhythmia, Hepatobilary: hepatitis, liver failure Hemic and Lymphatic: rectal blecding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Special Senses: blured vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria OVERDOSAGE Symptoms and Signs Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver fuction, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. The oral LDso of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs. Treatment Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding. DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and other treatment options before dcciding to use NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Use the lowest effectivc dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient's needs, 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation. Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the stomach, the absorption of the drug is delayed compared to the other naproxen formulations (see CLINICAL PHARMACOLOGY). The recommended strategy for initiating therapy is to choose a formulation and a staring dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS). Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, . the unbound plasma fraction of naproxen is increased in the eldcrly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest cffective dose. Patients With Moderate to Severe Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance ..30 mL/min) (see WARNINGS: Renal Effects). Rheumatoid Arthritis, Osteoarthritis and Ankylosin9 Spondylitis NAPROSYN 250 mg twice daily or 375 mg twice daily or 500 mg twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN 250 mg (10 mL/2 tsp) twice daily Suspension or 375 mg (15 mL/3 tsp) twice daily or 500 mg (20 mL/4 tsp) twice daily EC-NAPROSYN 375 mg twice daily or 500 mg twice daily 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) . To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. NAPROSYN Suspension should be shaken gently before use. During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffce for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY). Juvenile Arthritis The use of NAPROSYN Suspension is recommended for juvenile arthritis in children 2 years or older because it allows for more flexible dose titration based on the child's weight. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen (see CLINICAL PHARMACOLOGY). The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 mililiter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing ofNAPROSYN Suspension: Patient's Weight Dose Administered as 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly àbsorbed, ANAPROXIANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN may also be used but EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). Acute Gout The recommended starting dose is 750 mg of NAPROSYN followed by 250 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting dose of 825 mg followed by 275 mg cvery 8 hours. EC- NAPROSYN is not recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). HOW SUPPLIED NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on one side and scored on the other. Packaged in light-resistant bottles of100. . 100's (bottle): NDC 0004-6313-01. 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light-resistant bottles of 100. 100' s (bottle): NDC 0004-6314-01. 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other. Packaged in light-resistant bottles of 100. 100's (bottle): NDC 0004-6316-01. Store at 150 to 30°C (590 to 86°F) in well-closed containers; dispensc in light- resistant containers. NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28). Store at 150 to 30°C (590 to 86°F); avoid excessive heat, above 40°C (104°F). Dispense in light-resistant containers. Shake gently before use. EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. Packaged in light- resistant bottles of 100. 100's (bottle): NDC 0004-6415-01. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) 500 mg: white, oblong coated tablets imprintcd with NPR EC 500 on one side. Packaged in light-resistant bottles of 100. 100' s (bottle): NDC 0004-6416-01. Store at 150 to 30°C (590 to 86°F) in well-closed containers; dispense in light- resistant containers. ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with NPS-275 on one side. Packaged in bottles of 100. 100's (bottle): NDC 0004-6202-01. Store at 15°to 30°C (590 to 86°F) in well-closed containers. ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong.: shaped, engraved with NPS 550 on one side and scored on both sides. Packaged in bottles of 100. 100' s (bottle): NDC 0004-6203 -0 1. Store at 150 to 30°C (590 to 86°F) in well-closed containers. Revised: September 2007 Medication Guide for Non-steroidal Anti-Inflammatorv Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: . with longer use of NSAID medicines . in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)." NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: . can happen without warning symptoms 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSY~ (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) . may cause death The chance of a person getting an ulcer or bleeding increases with: . taking medicines called "corticosteroids" and "anticoagulants" . longer use . smoking . drinking alcohol . older age . having poor health NSAID medicines should only be used: . exactly as prescribed . at the lowest dose possible for your treatment . for the shortest time needed ! What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swellng, and heat (inflammation) from medical conditions such as: . different types of arthritis . menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: . if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine . for pain right before or after heart bypass surgery Tell your healthcare provider: . about all of your medical conditions. . about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your health care provider and pharmacist. . if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. . if you are breastfeeding. Talk to your doctor. 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: . heart attack . stroke . high blood pressure . heart failure from body swelling (fluid retention) . kidney problems including kidney failure . bleeding and ulcers in the stomach and intestine . low red blood cells (anemia) . life-threatcning skin reactions . life-threatening allergic reactions . liver problems including liver failure . asthma attacks in peoplc who have asthma Other side effects include: . stomach pain . constipation . diarrhea . gas . heartburn . nausea . vomiting . dizziness Get emergency help right away if you have any of the following symptoms: . shortness of breath or trouble breathing . chest pain . weakness in one part or side of your body . slurred speech . swellng of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: . nausea . more tired or weaker than usual . itching . your skin or eyes look yellow . stomach pain . flu-like symptoms . vomit blood . there is blood in your bowel movement or it is black and sticky like tar . unusual weight gain . skin rash or blisters with fever . swellng of the arms and legs, hands and feet These are not all the side effects with NSAID _me.dicines._Talk_ to_your - - healthcare provider or pharmacist for more information about NSAID medicines. 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): . Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. . Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcareprovider before using over-the-counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradenaiie Celecoxib Celebrex~ Diclofcnac Cataflam~, VoltarenCB, Arthrotec™ (combined with misoprostol) Diflunisal Dolobid~ Etodolac Lodine CB, Lodine CBXL Fenoprofen Nalfon~, Nalfon~200 Flurbirofen Ansaid~ Ibuprofen Motrin~, Tab-Profen~, VicoprofenCB (combined with hydrocodone), Combunox ™ (combined with oxycodone) Indomethacin IndocinCB, Indocin~SR, Indo-Lemmon™, Indomethagan ™ Ketoprofen Oruvail~ Ketorolac Toradol~ Mefenamic Acid Ponstel~ Meloxicam Mobic~ N abumetone Relafen ~ Naproxen NaprosynCB, AnaproxCB, Anaprox~DS, EC-NaprosynCB, Naprelan~, Naprapac~ (copackagcd with lansoprazole) Oxaprozin DayproCB Piroxicam Feldene~ Sulindac ClinorilCB Tolmetin Tolectin~, Tolectin DS~, TolectinCB600 *Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAID, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. Revised: January 2007 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) This Medication Guide has been approved by the U.S. Food and Drug Administration. All registered trademarks in this document are the property of their respective owners. Distributed by: (Roche) Pharmaceuticals Roche Laboratories Inc. 340 Kingsland Street Nutley, New Jersey 07110- 1199 xxxxxxxx XXXXXXXX Copyright (9 1999-2001 by Roche Laboratories Inc. All rights reserved. 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:09.125744	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017581s108,18164s58,18965s16,20067s14lbl.pdf', 'application_number': 18965, 'submission_type': 'SUPPL ', 'submission_number': 16}
11,391	NAPROSYN (naproxen) Suspension Rx only WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS).  NAPROSYN Suspension is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS, WARNINGS). Gastrointestinal Bleeding, Ulceration, and Perforation  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (see WARNINGS). DESCRIPTION Naproxen is a proprionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical name for naproxen is (S)-6-methoxy--methyl-2- naphthaleneacetic acid. Naproxen has the following structure: structural formula Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen is an odorless, white to off-white crystalline substance. It is lipid- soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. NAPROSYN Suspension is available as a light orange-colored opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle containing sucrose, magnesium aluminum silicate, sorbitol solution and sodium chloride (39 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified water. The pH of the suspension ranges from 2.2 to 3.7. Reference ID: 3928116 1 NAPROSYN (naproxen) Suspension CLINICAL PHARMACOLOGY Mechanism of Action Naproxen has analgesic, anti-inflammatory and antipyretic properties. The mechanism of action of naproxen, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Pharmacokinetics Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The elimination half-life of naproxen ranges from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half- life. Absorption Peak plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours. When NAPROSYN Suspension and immediate release naproxen tablets were given to fasted subjects (n=12) in a single-dose, crossover study, there were comparable pharmacokinetic parameters between the two formulation. NAPROSYN Naproxen Tablets Suspension 500 mg Cmax (µg/mL) Tmax (hours) T1/2 (hours) AUC0–t (µg·hr/mL) 64.3 2.6 16.8 1249 71.1 2.3 16.3 1218 Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher Reference ID: 3928116 2 NAPROSYN (naproxen) Suspension doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS; Nursing Mothers). Elimination Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate (see WARNINGS; Renal Toxicity and Hyperkalemia). Special Populations Pediatric Patients In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND ADMINISTRATION) were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of NAPROSYN suspension or tablets in pediatric patients. Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the Reference ID: 3928116 3 NAPROSYN (naproxen) Suspension increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Race Pharmacokinetic differences due to race have not been studied. Hepatic Impairment Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose. Renal Impairment Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS; Renal Toxicity and Hyperkalemia). Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin (see PRECAUTIONS; Drug Interactions). CLINICAL STUDIES General Information Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. Reference ID: 3928116 4 NAPROSYN (naproxen) Suspension In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg twice a day (750 mg a day) vs 750 mg twice a day (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of Reference ID: 3928116 5 NAPROSYN (naproxen) Suspension naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of NAPROSYN has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Geriatric Patients The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN Suspension. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation). NAPROSYN (naproxen) Suspension is indicated:  For the relief of the signs and symptoms of rheumatoid arthritis  For the relief of the signs and symptoms of osteoarthritis  For the relief of the signs and symptoms of ankylosing spondylitis  For the relief of the signs and symptoms of juvenile rheumatoid arthritis NAPROSYN (naproxen) Suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the patient’s weight. NAPROSYN (naproxen) Suspension is also indicated:  For relief of the signs and symptoms of tendonitis  For relief of the signs and symptoms of bursitis  For relief of the signs and symptoms of acute gout  For the management of pain Reference ID: 3928116 6 NAPROSYN (naproxen) Suspension  For the management of primary dysmenorrhea CONTRAINDICATIONS NAPROSYN Suspension is contraindicated in the following patients:  Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product (see WARNINGS; Anaphylactic Reactions, Serious Skin Reactions).  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS; Anaphylactic Reactions, Exacerbation of Asthma Related to Aspirin Sensitivity).  In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS; Cardiovascular Thrombotic Events). WARNINGS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events (see WARNINGS; Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation). Reference ID: 3928116 7 NAPROSYN (naproxen) Suspension Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next 4 years of follow-up. Avoid the use of NAPROSYN Suspension in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPROSYN Suspension is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk of developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, or anticoagulants, or selective serotonin reuptake inhibitors (SSRIs), smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports Reference ID: 3928116 8 NAPROSYN (naproxen) Suspension of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients:  Use the lowest effective dosage for the shortest possible duration.  Avoid administration of more than one NSAID at a time.  Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.  Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.  If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue NAPROSYN Suspension until a serious GI adverse event is ruled out.  In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding (see PRECAUTIONS; Drug Interactions). Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients taking NSAIDs including naproxen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NAPROSYN Suspension immediately, and perform a clinical evaluation of the patient. Hypertension NSAIDs, including NAPROSYN Suspension, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see PRECAUTIONS; Drug Interactions). Reference ID: 3928116 9 NAPROSYN (naproxen) Suspension Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention, and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] (see PRECAUTION; Drug Interactions). Avoid the use of NAPROSYN Suspension in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPROSYN Suspension is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Each 5 mL of NAPROSYN Suspension contains 39 mg of sodium. This should be considered in patients whose overall intake of sodium must be severely restricted. Renal Toxicity and Hyperkalemia Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of NAPROSYN Suspension in patients with advanced renal disease. The renal effects of NAPROSYN Suspension may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating Reference ID: 3928116 10 NAPROSYN (naproxen) Suspension NAPROSYN Suspension. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPROSYN Suspension (see PRECAUTIONS; Drug Interactions). Avoid the use of NAPROSYN Suspension in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPROSYN Suspension is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin- sensitive asthma (see CONTRAINDICATIONS, WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity). Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NAPROSYN Suspension is contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS). When NAPROSYN Suspension is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Serious Skin Reactions NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of NAPROSYN Suspension at the first appearance of skin rash or any other sign of hypersensitivity. NAPROSYN Suspension is contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS). Premature Closure of Fetal Ductus Arteriosus Naproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including NAPROSYN Suspension, in pregnant women starting at Reference ID: 3928116 11 NAPROSYN (naproxen) Suspension 30 weeks of gestation (third trimester) (see PRECAUTIONS; Pregnancy). Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with NAPROSYN Suspension has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including NAPROSYN Suspension, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding (see PRECAUTIONS; Drug Interactions). PRECAUTIONS General NAPROSYN Suspension should not be used concomitantly with other naproxen-containing products since they all circulate in the plasma as the naproxen anion. NAPROSYN Suspension cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. Patients with initial hemoglobin values of 10 g or less who are to receive long- term therapy should have hemoglobin values determined periodically. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with NAPROSYN Suspension and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic Reference ID: 3928116 12 NAPROSYN (naproxen) Suspension events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS; Cardiovascular Thrombotic Events). Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NAPROSYN Suspension and seek immediate medical therapy (see WARNINGS; Hepatotoxicity). Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS; Heart Failure and Edema). Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (see CONTRAINDICATIONS, WARNINGS; Anaphylactic Reactions). Serious Skin Reactions Advise patients to stop NAPROSYN Suspension immediately if they develop any type of rash and to contact their healthcare provider as soon as possible (see WARNINGS; Serious Skin Reactions). Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including NAPROSYN Suspension, may be associated with a reversible delay in ovulation (see PRECAUTIONS; Carcinogenesis, Mutagenesis, Impairment of Fertility). Reference ID: 3928116 13 NAPROSYN (naproxen) Suspension Fetal Toxicity Inform pregnant women to avoid use of NAPROSYN Suspension and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus (see WARNINGS; Premature Closure of Fetal Ductus Arteriosus). Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of NAPROSYN Suspension with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation and Drug Interactions, PRECAUTIONS; Drug Interactions). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with NAPROSYN Suspension until they talk to their healthcare provider (see PRECAUTIONS; Drug Interactions). Activities Requiring Alertness Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen. Masking of Inflammation and Fever The pharmacological activity of NAPROSYN in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, and Hepatotoxicity). Drug Interactions See Table 1 for clinically significant drug interactions with naproxen. Reference ID: 3928116 14 NAPROSYN (naproxen) Suspension Table 1: Clinically Significant Drug Interactions with naproxen Drugs That Interfere with Hemostasis Clinical • Naproxen and anticoagulants such as warfarin have a synergistic effect on Impact: bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of NAPROSYN Suspension with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity). Aspirin Clinical Controlled clinical studies showed that the concomitant use of NSAIDs and Impact: analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation). Intervention: Concomitant use of NAPROSYN Suspension and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). NAPROSYN Suspension is not a substitute for low dose aspirin for cardiovascular protection.[JP1] ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical • NSAIDs may diminish the antihypertensive effect of angiotensin converting Impact: enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of NAPROSYN Suspension and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of NAPROSYN Suspension and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Clinical studies, as well as post-marketing observations, showed that NSAIDs Impact: reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention During concomitant use of NAPROSYN Suspension with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic 15 Reference ID: 3928116 NAPROSYN (naproxen) Suspension efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia). Digoxin Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of NAPROSYN Suspension and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Suspension and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of NAPROSYN Suspension and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NAPROSYN Suspension and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of NAPROSYN Suspension and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation). Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NAPROSYN Suspension may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NAPROSYN Suspension and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacids and Sucralfate Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. 16 Reference ID: 3928116 NAPROSYN (naproxen) Suspension Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with NAPROSYN Suspension is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen. Intervention: Concomitant administration of cholestyramine with NAPROSYN Suspension is not recommended. Probenecid Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Intervention: Patients simultaneously receiving NAPROSYN Suspension and probenecid should be observed for adjustment of dose if required. Other albumin-bound drugs Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation). Intervention: Patients simultaneously receiving NAPROSYN Suspension and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interactions Bleeding times Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time. Intervention: This effect should be kept in mind when bleeding times are determined. Porter-Silber test Clinical Impact: The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Urinary assays of 5-hydroxy indoleacetic acid (5HIAA) Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. Carcinogenesis, mutagenesis, impairment of fertility Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found. 17 Reference ID: 3928116 NAPROSYN (naproxen) Suspension Mutagenesis Studies to evaluate the mutagenic potential of NAPROSYN Suspension have not been completed. Impairment of Fertility Studies to evaluate the impact of naproxen on male or female fertility have not been completed. Pregnancy Risk Summary Use of NSAIDs, including NAPROSYN Suspension, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including NAPROSYN Suspension, in pregnant women starting at 30 weeks of gestation (third trimester) (see WARNINGS; Premature Closure of Fetal Ductus Arterious). There are no adequate and well-controlled studies of NAPROSYN Suspension in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats, rabbit, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and post-implantation loss. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy starting at 30 weeks of gestation, or third trimester) Reference ID: 3928116 18 NAPROSYN (naproxen) Suspension should be avoided. Animal Data Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and post-implantation loss. Labor and Delivery There are no studies on the effects of NAPROSYN Suspension during labor or delivery. In animal studies, NSAIDs, including naproxen, inhibit prostaglandin synthesis, because delayed parturition, and increase the incidence of stillbirth. Nursing Mothers The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPROSYN Suspension and any potential adverse effects on the breastfed infant from the NAPROSYN Suspension or from the underlying maternal condition. Females and Males of Reproductive Potential Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPROSYN Suspension, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPROSYN Suspension, in women who have difficulties conceiving or who are undergoing investigation of infertility. Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have Reference ID: 3928116 19 NAPROSYN (naproxen) Suspension not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age (see DOSAGE AND ADMINISTRATION). Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID- associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hepatotoxicity, Renal Toxicity and Hyperkalemia, PRECAUTIONS; Laboratory Monitoring). Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). Naproxen 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. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs (see WARNINGS: Renal Toxicity and Hyperkalemia). ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events (see WARNINGS) • GI Bleeding, Ulceration and Perforation (see WARNINGS) Reference ID: 3928116 20 NAPROSYN (naproxen) Suspension • Hepatotoxicity (see WARNINGS) • Hypertension (see WARNINGS) • Heart Failure and Edema (see WARNINGS) • Renal Toxicity and Hyperkalemia (see WARNINGS) • Anaphylactic Reactions (see WARNINGS) • Serious Skin Reactions (see WARNINGS) • Hematologic Toxicity (see WARNINGS) Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen (see CLINICAL PHARMACOLOGY). In controlled clinical trials with about 80 pediatric patients and in well- monitored, open-label studies with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: edema, palpitations General: dyspnea, thirst Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. Reference ID: 3928116 21 NAPROSYN (naproxen) Suspension In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease). Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis, asthma Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine 22 Reference ID: 3928116 NAPROSYN (naproxen) Suspension Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria OVERDOSAGE Symptoms and Signs Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, epigastric pain, nausea, and vomiting, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hypertension, Renal Toxicity and Hyperkalemia). Treatment Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. C o n si d e r emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine or hemodialysis, o r hemoperfusion may not be useful 23 Reference ID: 3928116 NAPROSYN (naproxen) Suspension due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation). After observing the response to initial therapy with NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient’s needs. Different dose strengths and formulations (i.e., tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation. Although NAPROSYN Suspension and other formulations of naproxen and naproxen sodium all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen (see CLINICAL PHARMACOLOGY). The recommended strategy for initiating therapy is to choose a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS; Hepatotoxicity, and Renal Toxicity and Hyperkalemia, and PRECAUTIONS; Geriatric Use). Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. 24 Reference ID: 3928116 NAPROSYN (naproxen) Suspension Patients with Moderate to Severe Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Toxicity and Hyperkalemia). Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis NAPROSYN Suspension 250 mg (10 mL) twice daily or 375 mg (15 mL) twice daily or 500 mg (20 mL) twice daily NAPROSYN Suspension should be shaken gently before use. During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY). Juvenile Rheumatoid Arthritis The use of NAPROSYN Suspension is recommended for juvenile arthritis in children 2 years or older because it allows for more flexible dose titration based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen (see CLINICAL PHARMACOLOGY). The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (i.e., 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing of NAPROSYN Suspension: 25 Reference ID: 3928116 NAPROSYN (naproxen) Suspension Patient’s Weight Dose Administered as 13 kg (29 lb) 62.5 mg, twice daily 2.5 mL, twice daily 25 kg (55 lb) 125 mg, twice daily 5.0 mL, twice daily 38 kg (84 lb) 187.5 mg, twice daily 7.5 mL, twice daily Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose of NAPROSYN Suspension is 500 mg (20 mL), followed by 250 mg (10 mL) every 6 to 8 hours as required. The total daily dose should not exceed 1250 mg (50 mL) (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). Acute Gout The recommended starting dose is 750 mg of NAPROSYN Suspension followed by 250 mg every 8 hours until the attack has subsided (see CLINICAL PHARMACOLOGY). HOW SUPPLIED NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium): Available in 1 pint (473 mL) light-resistant bottles (NDC xxxxx-xxx-xx). Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). Dispense in light-resistant containers. Shake gently before use. Revised: May 2016 Reference ID: 3928116 26 NAPROSYN (naproxen) Suspension Medication Guide for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including:  Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.  Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o longer use of NSAIDs o smoking o drinking alcohol o older age o poor health o advanced liver disease o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps and other types of short- term pain. Who should not take NSAIDs? Do not take NSAIDs: 27 Reference ID: 3928116 NAPROSYN (naproxen) Suspension  if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.  right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:  have liver or kidney problems  have high blood pressure  have asthma  are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.  are breastfeeding or plan to breastfeed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?  new or worse high blood pressure  heart failure  liver problems including liver failure  kidney problems including kidney failure  low red blood cells (anemia)  life-threatening skin reactions  life threatening allergic reactions  Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms:  shortness of breath or trouble breathing  chest pain  weakness in one part or side of your body  slurred speech  swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: 28 Reference ID: 3928116 NAPROSYN (naproxen) Suspension  nausea  more tired or weaker than usual  diarrhea  itching  your skin or eyes look yellow  indigestion or stomach pain  flu-like symptoms  vomit blood  there is blood in your bowel movement or it is black and sticky like tar  unusual weight gain  skin rash or blisters with fever  swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Pediapharm Inc. at 1-8xx-xxx-xxxx. Other information about NSAIDs  Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.  Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured by: [manufacturer] Distributed by: Pediapharm Inc., [address] For More Information, go to www.xxx.xxx.com or call 1-8xx-xxx-xxxx. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: May 2016 29 Reference ID: 3928116	custom-source	2025-02-12T13:45:09.210974	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018965s022s023lbl.pdf', 'application_number': 18965, 'submission_type': 'SUPPL ', 'submission_number': 22}
11,392	NDA 18-972/S-030 Page 3  Cordarone (amiodarone HCl) TABLETS Rx only DESCRIPTION Cordarone is a member of a new class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams’ classification) effects, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride. It is not chemically related to any other available antiarrhythmic drug. The structural formula is as follows: Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. CLINICAL PHARMACOLOGY Electrophysiology/Mechanisms of Action In animals, Cordarone is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of Cordarone may be due to at least two major properties: 1) a prolongation of the myocardial cell-action potential duration and refractory period and 2) noncompetitive α- and β-adrenergic inhibition. Cordarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Cordarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Cordarone as they are evidence of its pharmacological action, although Cordarone can cause marked sinus bradycardia or sinus arrest and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 4 heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see “WARNINGS”). Hemodynamics In animal studies and after intravenous administration in man, Cordarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, Cordarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, Cordarone may have a mild negative inotropic effect. Pharmacokinetics Following oral administration in man, Cordarone is slowly and variably absorbed. The bioavailability of Cordarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of Cordarone. The effects of food upon the bioavailability of Cordarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the presence of food. Cordarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Cordarone, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA’s precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral Cordarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged. Although no dosage This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 5 adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Cordarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, Cordarone exhibited multi-compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Cordarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Cordarone should be based on individual patient requirements (see “DOSAGE AND ADMINISTRATION”). Cordarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk. Cordarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of Cordarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Cordarone is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence. Pharmacodynamics There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 6 pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects. Monitoring Effectiveness Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: 1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of Cordarone requires some provocative approach, either exercise or programmed electrical stimulation (PES). 2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by Cordarone (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in Cordarone patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Cordarone. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment. Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). While these issues remain unsettled for Cordarone, as for other agents, the prescriber of Cordarone should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of Cordarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Cordarone, the duration of follow-up, the dose of Cordarone, the use of additional antiarrhythmic agents, and many other factors. As Cordarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 7 to 15%. Overall arrhythmia-recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more. INDICATIONS AND USAGE Because of its life-threatening side effects and the substantial management difficulties associated with its use (see “WARNINGS” below), Cordarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated. 1. Recurrent ventricular fibrillation. 2. Recurrent hemodynamically unstable ventricular tachycardia. As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone (amiodarone HCl) Tablets favorably affects survival. Cordarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in-hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in the hospital. CONTRAINDICATIONS Cordarone is contraindicated in severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker). Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine. WARNINGS Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 8 seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur. Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried. Mortality In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months. Cordarone therapy was evaluated in two multi-centered, randomized, double-blind, placebo- controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post- MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows: Placebo Amiodarone Relative Risk N Deaths N Deaths 95%CI EMIAT 743 102 743 103 0.99 0.76-1.31 CAMIAT 596 68 606 57 0.88 0.58-1.16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 9 These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction). Pulmonary Toxicity There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral Cordarone with or without initial I.V. therapy. Findings have included pulmonary infiltrates on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Cordarone (amiodarone HCl) Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Cordarone therapy is initiated, a baseline chest X- ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months. Pulmonary toxicity secondary to Cordarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis or interstitial/alveolar pneumonitis, respectively. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with Cordarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Cordarone therapy discontinued in these patients. Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of Cordarone-induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on Cordarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of Cordarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the Cordarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with Cordarone at a lower dose has not resulted in return of toxicity. Reports suggest that the use of lower loading and maintenance doses of Cordarone are associated with a decreased incidence of Cordarone- induced pulmonary toxicity. In a patient receiving Cordarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 10 approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup. Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Cordarone therapy due to suspected drug- induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available. If a diagnosis of Cordarone-induced hypersensitivity pneumonitis is made, Cordarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone-induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Cordarone discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible. Worsened Arrhythmia Cordarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (torsades de pointes [TdP]). In addition, Cordarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “Drug Interactions, Other reported interactions with amiodarone”.) The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. A careful assessment of the potential risks and benefits of administering Cordarone must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients. Liver Injury Elevations of hepatic enzyme levels are seen frequently in patients exposed to Cordarone and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Cordarone or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with Cordarone. Loss of Vision This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 11 Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re- evaluation of Cordarone therapy. The risks and complications of antiarrhythmic therapy with Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Cordarone. (See “ADVERSE REACTIONS”). Neonatal Hypo- or Hyperthyroidism Cordarone can cause fetal harm when administered to a pregnant woman. Although Cordarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Cordarone is used during pregnancy, or if the patient becomes pregnant while taking Cordarone, the patient should be apprised of the potential hazard to the fetus. In general, Cordarone (amiodarone HCl) Tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus. In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (doses compared on a body surface area basis) PRECAUTIONS Impairment of Vision Optic Neuropathy and/or Neuritis Cases of optic neuropathy and optic neuritis have been reported (see “WARNINGS”). Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see “ADVERSE REACTIONS”). Neurologic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 12 Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete. Photosensitivity Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy. Thyroid Abnormalities Cordarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal. Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by Cordarone dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue Cordarone (amiodarone HCl) Tablets in some patients. Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of arrhythmia breakthrough or aggravation, which may result in death. In fact, IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone. The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Experience with thyroid surgery in this setting is extremely limited, and this form of therapy runs the theoretical risk of inducing thyroid storm. Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism. Surgery This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 13 Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics. Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship of this event to Cordarone therapy is unknown. Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone. Information for Patients Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document. Laboratory Tests Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone or discontinuing therapy. Cordarone alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid. Drug Interactions Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines (see “CLINICAL PHARMACOLOGY, Pharmacokinetics”). Amiodarone is also known to be an inhibitor of CYP3A4. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following: Protease inhibitors: Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 14 evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered. Histamine H2 antagonists: Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels. Other substances: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone (see “DOSAGE AND ADMINISTRATION”). Amiodarone may suppress certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes. Reported examples of this interaction include the following: Immunosuppressives: Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. HMG-CoA reductase inhibitors: Simvastatin (CYP3A4 substrate) in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis. Cardiovasculars: Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well. Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with oral amiodarone. There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 15 drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose. Antihypertensives: Amiodarone should be used with caution in patients receiving β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest. Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following: Antibiotics: Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone. Other substances, including herbal preparations: St. John’s Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving amiodarone could result in reduced amiodarone levels. Other reported interactions with amiodarone: Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 16 Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6. Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t½. Disopyramide increases QT prolongation which could cause arrhythmia. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “WARNINGS, Worsened Arrhythmia”.) Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil. Volatile Anesthetic Agents (See “PRECAUTIONS, Surgery, Volatile Anesthetic Agents.”) In addition to the interactions noted above, chronic (>2 weeks) oral Cordarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate. Electrolyte Disturbances Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during Cordarone therapy. Use caution when coadministering Cordarone with drugs which may induce hypokalemia and/or hypomagnesemia. Carcinogenesis, Mutagenesis, Impairment of Fertility Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative. In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (dose compared on a body surface area basis) Pregnancy: Pregnancy Category D See “WARNINGS, Neonatal Hypo- or Hyperthyroidism.” Labor and Delivery It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration of gestation or on parturition. Nursing Mothers This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 17 Cordarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered Cordarone have been shown to be less viable and have reduced body-weight gains. Therefore, when Cordarone therapy is indicated, the mother should be advised to discontinue nursing. Pediatric Use The safety and effectiveness of Cordarone (amiodarone HCl) Tablets in pediatric patients have not been established. Geriatric Use Clinical studies of Cordarone Tablets 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 Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see “WARNINGS”), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study. Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see “PRECAUTIONS”). Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high- dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses. Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See “WARNINGS.”) Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed. Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 18 Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug. The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days). The following side effects were each reported in 10 to 33% of patients: Gastrointestinal: Nausea and vomiting. The following side effects were each reported in 4 to 9% of patients: Dermatologic: Solar dermatitis/photosensitivity. Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias. Gastrointestinal: Constipation, anorexia. Ophthalmologic: Visual disturbances. Hepatic: Abnormal liver-function tests. Respiratory: Pulmonary inflammation or fibrosis. The following side effects were each reported in 1 to 3% of patients: Thyroid: Hypothyroidism, hyperthyroidism. Neurologic: Decreased libido, insomnia, headache, sleep disturbances. Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction. Gastrointestinal: Abdominal pain. Hepatic: Nonspecific hepatic disorders. Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities. The following side effects were each reported in less than 1% of patients: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities. In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism. Postmarketing Reports In postmarketing surveillance, sinus arrest, hepatitis, cholestatic hepatitis, cirrhosis, epididymitis, impotence, vasculitis, pseudotumor cerebri, syndrome of inappropriate antidiuretic hormone secretion (SIADH), thrombocytopenia, angioedema, bronchiolitis obliterans organizing pneumonia (possibly fatal), bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates, pleuritis, pancreatitis, toxic epidermal necrolysis (sometimes fatal), myopathy, muscle weakness, rhabdomyolysis, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, pruritus, hallucination, confusional state, disorientation, and delirium also have been reported in patients receiving Cordarone. OVERDOSAGE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 19 There have been cases, some fatal, of Cordarone overdose. In addition to general supportive measures, the patient’s cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone nor its metabolite is dialyzable. The acute oral LD50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg. DOSAGE AND ADMINISTRATION BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT. In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has not been determined. Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see “CLINICAL PHARMACOLOGY”). Individual patient titration is suggested according to the following guidelines: For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats. Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see “PRECAUTIONS, Drug Interactions”). Upon starting Cordarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on “Drug Interactions”). When adequate arrhythmia control is achieved, or if side effects become prominent, Cordarone dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see “CLINICAL PHARMACOLOGY–Monitoring Effectiveness”). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Cordarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see “CLINICAL PHARMACOLOGY”). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 20 The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient’s arrhythmia and response to therapy. When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of Cordarone and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below: Loading Dose Adjustment and Maintenance Dose (Daily) (Daily) Ventricular Arrhythmias 1 to 3 weeks ∼1 month usual maintenance 800 to 1,600 mg 600 to 800 mg 400 mg HOW SUPPLIED Cordarone (amiodarone HCl) Tablets are available in bottles of 60 tablets and in Redipak cartons containing 100 tablets (10 blister strips of 10) as follows: 200 mg, NDC 0008-4188, round, convex-faced, pink tablets with a raised “C” and marked “200” on one side, with reverse side scored and marked “WYETH” and “4188.” Keep tightly closed. Store at room temperature, approximately 25°C (77°F). Protect from light. Dispense in a light-resistant, tight container. Use carton to protect contents from light. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 21 Medication Guide Cordarone ′KOR-DU-RŌN Tablets (amiodarone HCl) Rx only Read the Medication Guide that comes with Cordarone Tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about Cordarone Tablets? Cordarone Tablets can cause serious side effects that can lead to death including: • lung damage • liver damage • worse heartbeat problems Call your doctor or get medical help right away if you have any symptoms such as the following: • shortness of breath, wheezing, or any other trouble breathing; coughing, chest pain, or spitting up of blood • nausea or vomiting; passing brown or dark-colored urine; feel more tired than usual; your skin and whites of your eyes get yellow; or have stomach pain • heart pounding, skipping a beat, beating very fast or very slowly; feel light-headed or faint Because of these possible side effects, Cordarone Tablets should only be used in adults with life- threatening heartbeat problems called ventricular arrhythmias, for which other treatments did not work or were not tolerated. Cordarone Tablets can cause other serious side effects. See “What are the possible or reasonably likely side effects of Cordarone Tablets?” for more information. If you get serious side effects during treatment with Cordarone Tablets you may need to stop Cordarone Tablets, have your dose changed, or get medical treatment. Talk with your doctor before you stop taking Cordarone Tablets. You may still have side effects after stopping Cordarone Tablets because the medicine stays in your body months after treatment is stopped. Tell all your healthcare providers that you take or took Cordarone Tablets. This information is very important for other medical treatments or surgeries you may have. What are Cordarone Tablets? This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 22 Cordarone is a medicine used in adults to treat life-threatening heartbeat problems called ventricular arrhythmias, for which other treatment did not work or was not tolerated. Cordarone Tablets have not been shown to help people with life-threatening heartbeat problems live longer. Treatment with Cordarone Tablets should be started in a hospital to monitor your condition. You should have regular check-ups, blood tests, chest x-rays, and eye exams before and during treatment with Cordarone Tablets to check for serious side effects. Cordarone Tablets have not been studied in children. Who should not take Cordarone Tablets? Do not take Cordarone Tablets if you: • have certain heart conditions (heart block, very slow heart rate, or slow heart rate with dizziness or lightheadedness) • have an allergy to amiodarone, iodine, or any of the other ingredients in Cordarone Tablets. See the end of this Medication Guide for a complete list of ingredients in Cordarone Tablets. What should I tell my doctor before starting Cordarone Tablets? Tell your doctor about all of your medical conditions including if you: • have lung or breathing problems • have liver problems • have or had thyroid problems • have blood pressure problems • are pregnant or planning to become pregnant. Cordarone can harm your unborn baby. Cordarone can stay in your body for months after treatment is stopped. Therefore, talk with your doctor before you plan to get pregnant. • are breastfeeding. Cordarone passes into your milk and can harm your baby. You should not breast feed while taking Cordarone. Also, Cordarone can stay in your body for months after treatment is stopped. Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Cordarone Tablets and certain other medicines can interact with each other causing serious side effects. Sometimes the dose of Cordarone Tablets or other medicines must be changed when they are used together. Especially, tell your doctor if you are taking: • antibiotic medicines used to treat infections • depression medicines • blood thinner medicines • HIV or AIDS medicines • cimetidine (Tagamet), a medicine for stomach ulcers or indigestion • seizure medicines • diabetes medicines • cyclosporine, an immunosuppressive medicine • dextromethorphan, a cough medicine • medicines for your heart, circulation, or blood pressure • water pills (diuretics) • high cholesterol or bile medicines • narcotic pain medicines • St. John’s Wort This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 23 Know the medicines you take. Keep a list of them with you at all times and show it to your doctor and pharmacist each time you get a new medicine. Do not take any new medicines while you are taking Cordarone Tablets unless you have talked with your doctor. How should I take Cordarone Tablets? • Take Cordarone Tablets exactly as prescribed by your doctor. • The dose of Cordarone Tablets you take has been specially chosen for you by your doctor and may change during treatment. Keep taking your medicine until your doctor tells you to stop. Do not stop taking it because you feel better. Your condition may get worse. Talk with your doctor if you have side effects. • Your doctor will tell you to take your dose of Cordarone Tablets with or without meals. Make sure you take Cordarone Tablets the same way each time. • Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach. • Taking too many Cordarone Tablets can be dangerous. If you take too many Cordarone Tablets, call your doctor or go to the nearest hospital right away. You may need medical care right away. • If you miss a dose, do not take a double dose to make up for the dose you missed. Continue with your next regularly scheduled dose. What should I avoid while taking Cordarone Tablets? • Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach. • Avoid exposing your skin to the sun or sun lamps. Cordarone Tablets can cause a photosensitive reaction. Wear sun-block cream or protective clothing when out in the sun. • Avoid pregnancy during treatment with Cordarone Tablets. Cordarone can harm your unborn baby. • Do not breastfeed while taking Cordarone Tablets. Cordarone passes into your milk and can harm your baby. What are the possible or reasonably likely side effects of Cordarone Tablets? Cordarone Tablets can cause serious side effects that lead to death including lung damage, liver damage, and worse heartbeat problems. See “What is the most important information I should know about Cordarone Tablets?” Some other serious side effects of Cordarone Tablets include: • vision problems that may lead to permanent blindness. You should have regular eye exams before and during treatment with Cordarone Tablets. Call your doctor if you have blurred vision, see halos, or your eyes become sensitive to light. • nerve problems. Cordarone Tablets can cause a feeling of “pins and needles” or numbness in the hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, and trouble walking. • thyroid problems. Cordarone Tablets can cause hypothyroidism or hyperthyroidism. Your doctor may arrange regular blood tests to check your thyroid function during treatment with Cordarone. Call your doctor if you have weight loss or weight gain, restlessness, weakness, heat or cold intolerance, hair thinning, sweating, changes in your menses, or swelling of your neck (goiter). • skin problems. Cordarone Tablets can cause your skin to be more sensitive to the sun or to turn a bluish-gray color. In most patients, skin color slowly returns to normal after stopping Cordarone Tablets. In some patients, skin color does not return to normal. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 24 Other side effects of Cordarone Tablets include nausea, vomiting, constipation, and loss of appetite. Call your doctor about any side effect that bothers you. These are not all the side effects with Cordarone Tablets. For more information, ask your doctor or pharmacist. How should I store Cordarone Tablets? • Store Cordarone Tablets at room temperature. Protect from light. Keep Cordarone Tablets in a tightly closed container. • Safely dispose of Cordarone Tablets that are out-of-date or no longer needed. • Keep Cordarone Tablets and all medicines out of the reach of children. General information about Cordarone Tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Cordarone Tablets for a condition for which it was not prescribed. Do not share Cordarone with other people, even if they have the same symptoms that you have. It may harm them. If you have any questions or concerns about Cordarone Tablets, ask your doctor or healthcare provider. This Medication Guide summarizes the most important information about Cordarone Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Cordarone Tablets that was written for healthcare professionals. This Medication Guide may have been revised after this copy was produced. For more information and the most current Medication Guide, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. What are the ingredients in Cordarone Tablets? Active Ingredient: amiodarone HCl Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rx only Manufactured for  Wyeth Laboratories A Wyeth-Ayerst Company Philadelphia, PA 19101 by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France Last Revised: August 2004 [PPI number] This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-030 Page 25 Based on Physician Insert W10427C005 Cordarone is a registered trademark of Sanofi-Synthelabo. Tagamet is a registered trademark of SmithKline Beecham Pharmaceuticals Co. 2004, Wyeth Pharmaceuticals. All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:09.389917	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18972s030lbl.pdf', 'application_number': 18972, 'submission_type': 'SUPPL ', 'submission_number': 30}
11,394	NDA 18-972/S-038/039 Page 3 Cordarone® (amiodarone HCl) Tablets Rx only DESCRIPTION Cordarone (amiodarone HCl) is a member of a new class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams' classification) effects, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2 (diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride. It is not chemically related to any other available antiarrhythmic drug. The structural formula is as follows: Chemical Structure Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. CLINICAL PHARMACOLOGY Electrophysiology/Mechanisms of Action In animals, Cordarone is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of Cordarone may be due to at least two major properties: 1. a prolongation of the myocardial cell-action potential duration and refractory period and 2. noncompetitive α- and β-adrenergic inhibition. Cordarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Cordarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Cordarone as they are evidence of its pharmacological action, although Cordarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see “WARNINGS”). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 4 Hemodynamics In animal studies and after intravenous administration in man, Cordarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, Cordarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, Cordarone may have a mild negative inotropic effect. Pharmacokinetics Following oral administration in man, Cordarone is slowly and variably absorbed. The bioavailability of Cordarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of Cordarone. The effects of food upon the bioavailability of Cordarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the presence of food. Cordarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Cordarone, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral Cordarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 5 Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Cordarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, Cordarone exhibited multi- compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Cordarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well- perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Cordarone should be based on individual patient requirements (see “DOSAGE AND ADMINISTRATION”). Cordarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk. Cordarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of Cordarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Cordarone is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 6 Pharmacodynamics There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects. Monitoring Effectiveness Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: 1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of Cordarone requires some provocative approach, either exercise or programmed electrical stimulation (PES). 2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by Cordarone (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in Cordarone patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Cordarone. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 7 Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). While these issues remain unsettled for Cordarone, as for other agents, the prescriber of Cordarone should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of Cordarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Cordarone, the duration of follow-up, the dose of Cordarone, the use of additional antiarrhythmic agents, and many other factors. As Cordarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia- recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more. INDICATIONS AND USAGE Because of its life-threatening side effects and the substantial management difficulties associated with its use (see “WARNINGS” below), Cordarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated. 1. Recurrent ventricular fibrillation. 2. Recurrent hemodynamically unstable ventricular tachycardia. As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone Tablets favorably affects survival. Cordarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in- hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in the hospital. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 8 CONTRAINDICATIONS Cordarone is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker). Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine. WARNINGS Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur. Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life- threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 9 Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried. Mortality In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months. Cordarone therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows: Placebo Amiodarone Relative Risk N Deaths N Deaths 95%CI EMIAT 743 102 743 103 0.99 0.76-1.31 CAMIAT 596 68 606 57 0.88 0.58-1.16 These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction). Pulmonary Toxicity There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral Cordarone with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Post-marketing reports describe cases of pulmonary toxicity in patients treated with low doses of Cordarone; however, reports suggest that the use of lower This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 10 loading and maintenance doses of Cordarone are associated with a decreased incidence of Cordarone-induced pulmonary toxicity. Cordarone Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Cordarone therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months. Pulmonary toxicity secondary to Cordarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis or interstitial/alveolar pneumonitis, respectively. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with Cordarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Cordarone therapy discontinued in these patients. Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of Cordarone induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on Cordarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of Cordarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the Cordarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with Cordarone at a lower dose has not resulted in return of toxicity. In a patient receiving Cordarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 11 Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Cordarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available. If a diagnosis of Cordarone-induced hypersensitivity pneumonitis is made, Cordarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Cordarone discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible. Worsened Arrhythmia Cordarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (torsades de pointes [TdP]). In addition, Cordarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly (See “Drug Interactions, Other reported interactions with amiodarone”). The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. A careful assessment of the potential risks and benefits of administering Cordarone must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 12 Implantable Cardiac Devices In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed. Thyrotoxicosis Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED (see “PRECAUTIONS, Thyroid Abnormalities”). Liver Injury Elevations of hepatic enzyme levels are seen frequently in patients exposed to Cordarone and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Cordarone or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with Cordarone. Loss of Vision Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of Cordarone therapy. The risks and complications of antiarrhythmic therapy with Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Cordarone (See “ADVERSE REACTIONS”). Neonatal Hypo- or Hyperthyroidism Cordarone can cause fetal harm when administered to a pregnant woman. Although Cordarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Cordarone is used during pregnancy, or if the patient becomes pregnant while taking Cordarone, the patient should be apprised of the potential hazard to the fetus. In general, Cordarone Tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 13 In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (doses compared on a body surface area basis) PRECAUTIONS Impairment of Vision Optic Neuropathy and/or Neuritis Cases of optic neuropathy and optic neuritis have been reported (see “WARNINGS”). Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see “ADVERSE REACTIONS”). Neurologic Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete. Photosensitivity Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 14 Thyroid Abnormalities Cordarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal. Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by Cordarone dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue Cordarone Tablets in some patients. Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone. The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see “WARNINGS, Thyrotoxicosis”). When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 15 amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with Cordarone. In some instances hyperthyroidism was also present (see “WARNINGS” and “ADVERSE REACTIONS”). Surgery Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics. Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship of this event to Cordarone therapy is unknown. Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone. Corneal Refractive Laser Surgery Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Cordarone. Information for Patients Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document. Laboratory Tests Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone or discontinuing therapy. Cordarone alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 16 Drug Interactions Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines (see “CLINICAL PHARMACOLOGY, Pharmacokinetics”). Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half- life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following: Protease inhibitors: Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered. Histamine H1 antagonists: Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of loratadine and amiodarone. Histamine H2 antagonists: Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels. Antidepressants: Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of trazodone and amiodarone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 17 Other substances: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4 mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone (see “DOSAGE AND ADMINISTRATION”). Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following: Immunosuppressives: Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. HMG-CoA reductase inhibitors: HMG-CoA reductase inhibitors that are CYP3A4 substrates (including simvastatin and atorvastatin) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis. When co-administered with amiodarone, lower starting and maintenance doses of these agents should be considered. Cardiovasculars: Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well. Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with oral amiodarone. There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 18 levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose. Antihypertensives: Amiodarone should be used with caution in patients receiving β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest. Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Cordarone resulting in ineffective inhibition of platelet aggregation has been reported. Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 19 Antibiotics: Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone. Other substances, including herbal preparations: St. John's Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving amiodarone could result in reduced amiodarone levels. Other reported interactions with amiodarone: Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone. Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6. Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t½. Disopyramide increases QT prolongation which could cause arrhythmia. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “WARNINGS, Worsened Arrhythmia”.) Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil. Volatile Anesthetic Agents (See “PRECAUTIONS, Surgery, Volatile Anesthetic Agents”). In addition to the interactions noted above, chronic (>2 weeks) oral Cordarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate. Electrolyte Disturbances Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during Cordarone therapy. Use caution when coadministering Cordarone with drugs which may induce hypokalemia and/or hypomagnesemia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 20 Carcinogenesis, Mutagenesis, Impairment of Fertility Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative. In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (dose compared on a body surface area basis) Pregnancy: Pregnancy Category D See “WARNINGS, Neonatal Hypo- or Hyperthyroidism”. Labor and Delivery It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration of gestation or on parturition. Nursing Mothers Cordarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered Cordarone have been shown to be less viable and have reduced body-weight gains. Therefore, when Cordarone therapy is indicated, the mother should be advised to discontinue nursing. Pediatric Use The safety and effectiveness of Cordarone Tablets in pediatric patients have not been established. Geriatric Use Clinical studies of Cordarone Tablets 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 label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 21 ADVERSE REACTIONS Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see “WARNINGS”), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study. Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see “PRECAUTIONS”). Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses. Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See “WARNINGS”.) Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed. Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only. Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug. The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 22 The following side effects were each reported in 10 to 33% of patients: Gastrointestinal: Nausea and vomiting. The following side effects were each reported in 4 to 9% of patients: Dermatologic: Solar dermatitis/photosensitivity. Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias. Gastrointestinal: Constipation, anorexia. Ophthalmologic: Visual disturbances. Hepatic: Abnormal liver-function tests. Respiratory: Pulmonary inflammation or fibrosis. The following side effects were each reported in 1 to 3% of patients: Thyroid: Hypothyroidism, hyperthyroidism. Neurologic: Decreased libido, insomnia, headache, sleep disturbances. Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction. Gastrointestinal: Abdominal pain. Hepatic: Nonspecific hepatic disorders. Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities. The following side effects were each reported in less than 1% of patients: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities. In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism. Postmarketing Reports In postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 23 necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, hallucination, confusional state, disorientation, delirium, epididymitis, and impotence, also have been reported with amiodarone therapy. OVERDOSAGE There have been cases, some fatal, of Cordarone overdose. In addition to general supportive measures, the patient's cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone nor its metabolite is dialyzable. The acute oral LD50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg. DOSAGE AND ADMINISTRATION BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT. In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has not been determined. Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see “CLINICAL PHARMACOLOGY”). Individual patient titration is suggested according to the following guidelines: For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats. Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 24 not be taken during treatment with oral amiodarone (see “PRECAUTIONS, Drug Interactions”). Upon starting Cordarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on “Drug Interactions”). When adequate arrhythmia control is achieved, or if side effects become prominent, Cordarone dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see “CLINICAL PHARMACOLOGY–Monitoring Effectiveness”). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Cordarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see “CLINICAL PHARMACOLOGY”). The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient's arrhythmia and response to therapy. When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of Cordarone and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below: Loading Dose (Daily) Adjustment and Maintenance Dose (Daily) Ventricular Arrhythmias 1 to 3 weeks ~1 month usual maintenance 800 to 1,600 mg 600 to 800 mg 400 mg HOW SUPPLIED Cordarone® (amiodarone HCl) Tablets are available in bottles of 60 tablets as follows: 200 mg, NDC 0008-4188-04, round, convex-faced, pink tablets with a raised “C” and marked “200” on one side, with reverse side scored and marked “WYETH” and “4188.” Keep tightly closed. Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F). Protect from light. Dispense in a light-resistant, tight container. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 25 Illustration Cpu This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Illustration Telephone This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 26 Medication Guide Cordarone® ′KOR-DU-RŌN Tablets (amiodarone HCl) Rx only Read the Medication Guide that comes with Cordarone Tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about Cordarone Tablets? Cordarone Tablets can cause serious side effects that can lead to death including: • lung damage • liver damage • worse heartbeat problems • thyroid problems Call your doctor or get medical help right away if you have any symptoms such as the following: • shortness of breath, wheezing, or any other trouble breathing; coughing, chest pain, or spitting up of blood • nausea or vomiting; passing brown or dark-colored urine; feel more tired than usual; your skin and whites of your eyes get yellow; or have stomach pain • heart pounding, skipping a beat, beating very fast or very slowly; feel light-headed or faint • weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor. Because of these possible side effects, Cordarone Tablets should only be used in adults with life-threatening heartbeat problems called ventricular arrhythmias, for which other treatments did not work or were not tolerated. Cordarone Tablets can cause other serious side effects. See “What are the possible or reasonably likely side effects of Cordarone Tablets?” for more information. If you get serious side effects during treatment with Cordarone Tablets you may need to stop Cordarone Tablets, have your dose changed, or get medical treatment. Talk with your doctor before you stop taking Cordarone Tablets. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 27 You may still have side effects after stopping Cordarone Tablets because the medicine stays in your body months after treatment is stopped. Tell all your healthcare providers that you take or took Cordarone Tablets. This information is very important for other medical treatments or surgeries you may have. What are Cordarone Tablets? Cordarone is a medicine used in adults to treat life-threatening heartbeat problems called ventricular arrhythmias, for which other treatment did not work or was not tolerated. Cordarone Tablets have not been shown to help people with life-threatening heartbeat problems live longer. Treatment with Cordarone Tablets should be started in a hospital to monitor your condition. You should have regular check-ups, blood tests, chest x-rays, and eye exams before and during treatment with Cordarone Tablets to check for serious side effects. Cordarone Tablets have not been studied in children. Who should not take Cordarone Tablets? Do not take Cordarone Tablets if you: • have certain heart conditions (heart block, very slow heart rate, or slow heart rate with dizziness or lightheadedness) • have an allergy to amiodarone, iodine, or any of the other ingredients in Cordarone Tablets. See the end of this Medication Guide for a complete list of ingredients in Cordarone Tablets. What should I tell my doctor before starting Cordarone Tablets? Tell your doctor about all of your medical conditions including if you: • have lung or breathing problems • have liver problems • have or had thyroid problems • have blood pressure problems • are pregnant or planning to become pregnant. Cordarone can harm your unborn baby. Cordarone can stay in your body for months after treatment is stopped. Therefore, talk with your doctor before you plan to get pregnant. • are breastfeeding. Cordarone passes into your milk and can harm your baby. You should not breast feed while taking Cordarone. Also, Cordarone can stay in your body for months after treatment is stopped. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 28 Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Cordarone Tablets and certain other medicines can interact with each other causing serious side effects. Sometimes the dose of Cordarone Tablets or other medicines must be changed when they are used together. Especially, tell your doctor if you are taking: • antibiotic medicines used to treat infections • depression medicines • blood thinner medicines • HIV or AIDS medicines • cimetidine (Tagamet®), a medicine for stomach ulcers or indigestion • loratadine (for example: Claritin®, Alavert®), a medicine for allergy symptoms • seizure medicines • diabetes medicines • cyclosporine, an immunosuppressive medicine • dextromethorphan, a cough medicine • medicines for your heart, circulation, or blood pressure • water pills (diuretics) • high cholesterol or bile medicines • narcotic pain medicines • St. John's Wort Know the medicines you take. Keep a list of them with you at all times and show it to your doctor and pharmacist each time you get a new medicine. Do not take any new medicines while you are taking Cordarone Tablets unless you have talked with your doctor. How should I take Cordarone Tablets? • Take Cordarone Tablets exactly as prescribed by your doctor. • The dose of Cordarone Tablets you take has been specially chosen for you by your doctor and may change during treatment. Keep taking your medicine until your doctor tells you to stop. Do not stop taking it because you feel better. Your condition may get worse. Talk with your doctor if you have side effects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 29 • Your doctor will tell you to take your dose of Cordarone Tablets with or without meals. Make sure you take Cordarone Tablets the same way each time. • Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach. • Taking too many Cordarone Tablets can be dangerous. If you take too many Cordarone Tablets, call your doctor or go to the nearest hospital right away. You may need medical care right away. • If you miss a dose, do not take a double dose to make up for the dose you missed. Continue with your next regularly scheduled dose. What should I avoid while taking Cordarone Tablets? • Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach. • Avoid exposing your skin to the sun or sun lamps. Cordarone Tablets can cause a photosensitive reaction. Wear sun-block cream or protective clothing when out in the sun. • Avoid pregnancy during treatment with Cordarone Tablets. Cordarone can harm your unborn baby. • Do not breastfeed while taking Cordarone Tablets. Cordarone passes into your milk and can harm your baby. What are the possible or reasonably likely side effects of Cordarone Tablets? Cordarone Tablets can cause serious side effects that lead to death including lung damage, liver damage, worse heartbeat problems, and thyroid problems. See “What is the most important information I should know about Cordarone Tablets?” Some other serious side effects of Cordarone Tablets include: • vision problems that may lead to permanent blindness. You should have regular eye exams before and during treatment with Cordarone Tablets. Call your doctor if you have blurred vision, see halos, or your eyes become sensitive to light. • nerve problems. Cordarone Tablets can cause a feeling of “pins and needles” or numbness in the hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, and trouble walking. • thyroid problems. Cordarone Tablets can cause thyroid problems, including low thyroid function or overactive thyroid function. Your doctor may arrange regular blood tests to check your thyroid function during treatment with Cordarone. Call your doctor if you have weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 30 sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor. • skin problems. Cordarone Tablets can cause your skin to be more sensitive to the sun or to turn a bluish-gray color. In most patients, skin color slowly returns to normal after stopping Cordarone Tablets. In some patients, skin color does not return to normal. Other side effects of Cordarone Tablets include nausea, vomiting, constipation, and loss of appetite. Call your doctor about any side effect that bothers you. These are not all the side effects with Cordarone Tablets. For more information, ask your doctor or pharmacist. How should I store Cordarone Tablets? • Store Cordarone Tablets at room temperature. Protect from light. Keep Cordarone Tablets in a tightly closed container. • Safely dispose of Cordarone Tablets that are out-of-date or no longer needed. • Keep Cordarone Tablets and all medicines out of the reach of children. General information about Cordarone Tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Cordarone Tablets for a condition for which it was not prescribed. Do not share Cordarone with other people, even if they have the same symptoms that you have. It may harm them. If you have any questions or concerns about Cordarone Tablets, ask your doctor or healthcare provider. This Medication Guide summarizes the most important information about Cordarone Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Cordarone Tablets that was written for healthcare professionals. Illustration Cpu This Medication Guide may have been revised after this copy was produced. For more information and the most current Medication Guide, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Illustration Telephone What are the ingredients in Cordarone Tablets? Active Ingredient: amiodarone HCl This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 31 Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rx only Manufactured for Wyeth® Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France Cordarone is a registered trademark of Sanofi-Synthelabo. Tagamet is a registered trademark of SmithKline Beecham Pharmaceuticals Co. Claritin is a registered trademark of Schering Corporation. Alavert is a registered trademark of Wyeth. ©2004, Wyeth Pharmaceuticals. All rights reserved. (Update W10427C017) (Update ET01) (Update Rev Date) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:09.727490	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018972s038s039lbl.pdf', 'application_number': 18972, 'submission_type': 'SUPPL ', 'submission_number': 39}
11,393	NDA 18-972/S-038/039 Page 3 Cordarone® (amiodarone HCl) Tablets Rx only DESCRIPTION Cordarone (amiodarone HCl) is a member of a new class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams' classification) effects, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2 (diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride. It is not chemically related to any other available antiarrhythmic drug. The structural formula is as follows: Chemical Structure Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. CLINICAL PHARMACOLOGY Electrophysiology/Mechanisms of Action In animals, Cordarone is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of Cordarone may be due to at least two major properties: 1. a prolongation of the myocardial cell-action potential duration and refractory period and 2. noncompetitive α- and β-adrenergic inhibition. Cordarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Cordarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Cordarone as they are evidence of its pharmacological action, although Cordarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see “WARNINGS”). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 4 Hemodynamics In animal studies and after intravenous administration in man, Cordarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, Cordarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, Cordarone may have a mild negative inotropic effect. Pharmacokinetics Following oral administration in man, Cordarone is slowly and variably absorbed. The bioavailability of Cordarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of Cordarone. The effects of food upon the bioavailability of Cordarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the presence of food. Cordarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Cordarone, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral Cordarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 5 Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Cordarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, Cordarone exhibited multi- compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Cordarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well- perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Cordarone should be based on individual patient requirements (see “DOSAGE AND ADMINISTRATION”). Cordarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk. Cordarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of Cordarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Cordarone is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 6 Pharmacodynamics There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects. Monitoring Effectiveness Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: 1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of Cordarone requires some provocative approach, either exercise or programmed electrical stimulation (PES). 2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by Cordarone (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in Cordarone patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Cordarone. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 7 Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). While these issues remain unsettled for Cordarone, as for other agents, the prescriber of Cordarone should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of Cordarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Cordarone, the duration of follow-up, the dose of Cordarone, the use of additional antiarrhythmic agents, and many other factors. As Cordarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia- recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more. INDICATIONS AND USAGE Because of its life-threatening side effects and the substantial management difficulties associated with its use (see “WARNINGS” below), Cordarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated. 1. Recurrent ventricular fibrillation. 2. Recurrent hemodynamically unstable ventricular tachycardia. As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone Tablets favorably affects survival. Cordarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in- hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in the hospital. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 8 CONTRAINDICATIONS Cordarone is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker). Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine. WARNINGS Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur. Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life- threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 9 Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried. Mortality In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months. Cordarone therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows: Placebo Amiodarone Relative Risk N Deaths N Deaths 95%CI EMIAT 743 102 743 103 0.99 0.76-1.31 CAMIAT 596 68 606 57 0.88 0.58-1.16 These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction). Pulmonary Toxicity There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral Cordarone with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Post-marketing reports describe cases of pulmonary toxicity in patients treated with low doses of Cordarone; however, reports suggest that the use of lower This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 10 loading and maintenance doses of Cordarone are associated with a decreased incidence of Cordarone-induced pulmonary toxicity. Cordarone Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Cordarone therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months. Pulmonary toxicity secondary to Cordarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis or interstitial/alveolar pneumonitis, respectively. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with Cordarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Cordarone therapy discontinued in these patients. Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of Cordarone induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on Cordarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of Cordarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the Cordarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with Cordarone at a lower dose has not resulted in return of toxicity. In a patient receiving Cordarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 11 Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Cordarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available. If a diagnosis of Cordarone-induced hypersensitivity pneumonitis is made, Cordarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Cordarone discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible. Worsened Arrhythmia Cordarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (torsades de pointes [TdP]). In addition, Cordarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly (See “Drug Interactions, Other reported interactions with amiodarone”). The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. A careful assessment of the potential risks and benefits of administering Cordarone must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 12 Implantable Cardiac Devices In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed. Thyrotoxicosis Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED (see “PRECAUTIONS, Thyroid Abnormalities”). Liver Injury Elevations of hepatic enzyme levels are seen frequently in patients exposed to Cordarone and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Cordarone or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with Cordarone. Loss of Vision Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of Cordarone therapy. The risks and complications of antiarrhythmic therapy with Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Cordarone (See “ADVERSE REACTIONS”). Neonatal Hypo- or Hyperthyroidism Cordarone can cause fetal harm when administered to a pregnant woman. Although Cordarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Cordarone is used during pregnancy, or if the patient becomes pregnant while taking Cordarone, the patient should be apprised of the potential hazard to the fetus. In general, Cordarone Tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 13 In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (doses compared on a body surface area basis) PRECAUTIONS Impairment of Vision Optic Neuropathy and/or Neuritis Cases of optic neuropathy and optic neuritis have been reported (see “WARNINGS”). Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see “ADVERSE REACTIONS”). Neurologic Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete. Photosensitivity Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 14 Thyroid Abnormalities Cordarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal. Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by Cordarone dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue Cordarone Tablets in some patients. Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone. The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see “WARNINGS, Thyrotoxicosis”). When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 15 amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with Cordarone. In some instances hyperthyroidism was also present (see “WARNINGS” and “ADVERSE REACTIONS”). Surgery Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics. Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship of this event to Cordarone therapy is unknown. Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone. Corneal Refractive Laser Surgery Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Cordarone. Information for Patients Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document. Laboratory Tests Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone or discontinuing therapy. Cordarone alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 16 Drug Interactions Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines (see “CLINICAL PHARMACOLOGY, Pharmacokinetics”). Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half- life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following: Protease inhibitors: Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered. Histamine H1 antagonists: Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of loratadine and amiodarone. Histamine H2 antagonists: Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels. Antidepressants: Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of trazodone and amiodarone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 17 Other substances: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4 mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone (see “DOSAGE AND ADMINISTRATION”). Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following: Immunosuppressives: Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. HMG-CoA reductase inhibitors: HMG-CoA reductase inhibitors that are CYP3A4 substrates (including simvastatin and atorvastatin) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis. When co-administered with amiodarone, lower starting and maintenance doses of these agents should be considered. Cardiovasculars: Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well. Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with oral amiodarone. There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 18 levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose. Antihypertensives: Amiodarone should be used with caution in patients receiving β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest. Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Cordarone resulting in ineffective inhibition of platelet aggregation has been reported. Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 19 Antibiotics: Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone. Other substances, including herbal preparations: St. John's Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving amiodarone could result in reduced amiodarone levels. Other reported interactions with amiodarone: Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone. Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6. Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t½. Disopyramide increases QT prolongation which could cause arrhythmia. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “WARNINGS, Worsened Arrhythmia”.) Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil. Volatile Anesthetic Agents (See “PRECAUTIONS, Surgery, Volatile Anesthetic Agents”). In addition to the interactions noted above, chronic (>2 weeks) oral Cordarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate. Electrolyte Disturbances Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during Cordarone therapy. Use caution when coadministering Cordarone with drugs which may induce hypokalemia and/or hypomagnesemia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 20 Carcinogenesis, Mutagenesis, Impairment of Fertility Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative. In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (dose compared on a body surface area basis) Pregnancy: Pregnancy Category D See “WARNINGS, Neonatal Hypo- or Hyperthyroidism”. Labor and Delivery It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration of gestation or on parturition. Nursing Mothers Cordarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered Cordarone have been shown to be less viable and have reduced body-weight gains. Therefore, when Cordarone therapy is indicated, the mother should be advised to discontinue nursing. Pediatric Use The safety and effectiveness of Cordarone Tablets in pediatric patients have not been established. Geriatric Use Clinical studies of Cordarone Tablets 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 label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 21 ADVERSE REACTIONS Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see “WARNINGS”), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study. Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see “PRECAUTIONS”). Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses. Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See “WARNINGS”.) Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed. Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only. Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug. The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 22 The following side effects were each reported in 10 to 33% of patients: Gastrointestinal: Nausea and vomiting. The following side effects were each reported in 4 to 9% of patients: Dermatologic: Solar dermatitis/photosensitivity. Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias. Gastrointestinal: Constipation, anorexia. Ophthalmologic: Visual disturbances. Hepatic: Abnormal liver-function tests. Respiratory: Pulmonary inflammation or fibrosis. The following side effects were each reported in 1 to 3% of patients: Thyroid: Hypothyroidism, hyperthyroidism. Neurologic: Decreased libido, insomnia, headache, sleep disturbances. Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction. Gastrointestinal: Abdominal pain. Hepatic: Nonspecific hepatic disorders. Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities. The following side effects were each reported in less than 1% of patients: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities. In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism. Postmarketing Reports In postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 23 necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, hallucination, confusional state, disorientation, delirium, epididymitis, and impotence, also have been reported with amiodarone therapy. OVERDOSAGE There have been cases, some fatal, of Cordarone overdose. In addition to general supportive measures, the patient's cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone nor its metabolite is dialyzable. The acute oral LD50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg. DOSAGE AND ADMINISTRATION BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT. In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has not been determined. Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see “CLINICAL PHARMACOLOGY”). Individual patient titration is suggested according to the following guidelines: For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats. Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 24 not be taken during treatment with oral amiodarone (see “PRECAUTIONS, Drug Interactions”). Upon starting Cordarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on “Drug Interactions”). When adequate arrhythmia control is achieved, or if side effects become prominent, Cordarone dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see “CLINICAL PHARMACOLOGY–Monitoring Effectiveness”). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Cordarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see “CLINICAL PHARMACOLOGY”). The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient's arrhythmia and response to therapy. When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of Cordarone and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below: Loading Dose (Daily) Adjustment and Maintenance Dose (Daily) Ventricular Arrhythmias 1 to 3 weeks ~1 month usual maintenance 800 to 1,600 mg 600 to 800 mg 400 mg HOW SUPPLIED Cordarone® (amiodarone HCl) Tablets are available in bottles of 60 tablets as follows: 200 mg, NDC 0008-4188-04, round, convex-faced, pink tablets with a raised “C” and marked “200” on one side, with reverse side scored and marked “WYETH” and “4188.” Keep tightly closed. Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F). Protect from light. Dispense in a light-resistant, tight container. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 25 Illustration Cpu This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Illustration Telephone This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 26 Medication Guide Cordarone® ′KOR-DU-RŌN Tablets (amiodarone HCl) Rx only Read the Medication Guide that comes with Cordarone Tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about Cordarone Tablets? Cordarone Tablets can cause serious side effects that can lead to death including: • lung damage • liver damage • worse heartbeat problems • thyroid problems Call your doctor or get medical help right away if you have any symptoms such as the following: • shortness of breath, wheezing, or any other trouble breathing; coughing, chest pain, or spitting up of blood • nausea or vomiting; passing brown or dark-colored urine; feel more tired than usual; your skin and whites of your eyes get yellow; or have stomach pain • heart pounding, skipping a beat, beating very fast or very slowly; feel light-headed or faint • weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor. Because of these possible side effects, Cordarone Tablets should only be used in adults with life-threatening heartbeat problems called ventricular arrhythmias, for which other treatments did not work or were not tolerated. Cordarone Tablets can cause other serious side effects. See “What are the possible or reasonably likely side effects of Cordarone Tablets?” for more information. If you get serious side effects during treatment with Cordarone Tablets you may need to stop Cordarone Tablets, have your dose changed, or get medical treatment. Talk with your doctor before you stop taking Cordarone Tablets. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 27 You may still have side effects after stopping Cordarone Tablets because the medicine stays in your body months after treatment is stopped. Tell all your healthcare providers that you take or took Cordarone Tablets. This information is very important for other medical treatments or surgeries you may have. What are Cordarone Tablets? Cordarone is a medicine used in adults to treat life-threatening heartbeat problems called ventricular arrhythmias, for which other treatment did not work or was not tolerated. Cordarone Tablets have not been shown to help people with life-threatening heartbeat problems live longer. Treatment with Cordarone Tablets should be started in a hospital to monitor your condition. You should have regular check-ups, blood tests, chest x-rays, and eye exams before and during treatment with Cordarone Tablets to check for serious side effects. Cordarone Tablets have not been studied in children. Who should not take Cordarone Tablets? Do not take Cordarone Tablets if you: • have certain heart conditions (heart block, very slow heart rate, or slow heart rate with dizziness or lightheadedness) • have an allergy to amiodarone, iodine, or any of the other ingredients in Cordarone Tablets. See the end of this Medication Guide for a complete list of ingredients in Cordarone Tablets. What should I tell my doctor before starting Cordarone Tablets? Tell your doctor about all of your medical conditions including if you: • have lung or breathing problems • have liver problems • have or had thyroid problems • have blood pressure problems • are pregnant or planning to become pregnant. Cordarone can harm your unborn baby. Cordarone can stay in your body for months after treatment is stopped. Therefore, talk with your doctor before you plan to get pregnant. • are breastfeeding. Cordarone passes into your milk and can harm your baby. You should not breast feed while taking Cordarone. Also, Cordarone can stay in your body for months after treatment is stopped. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 28 Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Cordarone Tablets and certain other medicines can interact with each other causing serious side effects. Sometimes the dose of Cordarone Tablets or other medicines must be changed when they are used together. Especially, tell your doctor if you are taking: • antibiotic medicines used to treat infections • depression medicines • blood thinner medicines • HIV or AIDS medicines • cimetidine (Tagamet®), a medicine for stomach ulcers or indigestion • loratadine (for example: Claritin®, Alavert®), a medicine for allergy symptoms • seizure medicines • diabetes medicines • cyclosporine, an immunosuppressive medicine • dextromethorphan, a cough medicine • medicines for your heart, circulation, or blood pressure • water pills (diuretics) • high cholesterol or bile medicines • narcotic pain medicines • St. John's Wort Know the medicines you take. Keep a list of them with you at all times and show it to your doctor and pharmacist each time you get a new medicine. Do not take any new medicines while you are taking Cordarone Tablets unless you have talked with your doctor. How should I take Cordarone Tablets? • Take Cordarone Tablets exactly as prescribed by your doctor. • The dose of Cordarone Tablets you take has been specially chosen for you by your doctor and may change during treatment. Keep taking your medicine until your doctor tells you to stop. Do not stop taking it because you feel better. Your condition may get worse. Talk with your doctor if you have side effects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 29 • Your doctor will tell you to take your dose of Cordarone Tablets with or without meals. Make sure you take Cordarone Tablets the same way each time. • Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach. • Taking too many Cordarone Tablets can be dangerous. If you take too many Cordarone Tablets, call your doctor or go to the nearest hospital right away. You may need medical care right away. • If you miss a dose, do not take a double dose to make up for the dose you missed. Continue with your next regularly scheduled dose. What should I avoid while taking Cordarone Tablets? • Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach. • Avoid exposing your skin to the sun or sun lamps. Cordarone Tablets can cause a photosensitive reaction. Wear sun-block cream or protective clothing when out in the sun. • Avoid pregnancy during treatment with Cordarone Tablets. Cordarone can harm your unborn baby. • Do not breastfeed while taking Cordarone Tablets. Cordarone passes into your milk and can harm your baby. What are the possible or reasonably likely side effects of Cordarone Tablets? Cordarone Tablets can cause serious side effects that lead to death including lung damage, liver damage, worse heartbeat problems, and thyroid problems. See “What is the most important information I should know about Cordarone Tablets?” Some other serious side effects of Cordarone Tablets include: • vision problems that may lead to permanent blindness. You should have regular eye exams before and during treatment with Cordarone Tablets. Call your doctor if you have blurred vision, see halos, or your eyes become sensitive to light. • nerve problems. Cordarone Tablets can cause a feeling of “pins and needles” or numbness in the hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, and trouble walking. • thyroid problems. Cordarone Tablets can cause thyroid problems, including low thyroid function or overactive thyroid function. Your doctor may arrange regular blood tests to check your thyroid function during treatment with Cordarone. Call your doctor if you have weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 30 sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor. • skin problems. Cordarone Tablets can cause your skin to be more sensitive to the sun or to turn a bluish-gray color. In most patients, skin color slowly returns to normal after stopping Cordarone Tablets. In some patients, skin color does not return to normal. Other side effects of Cordarone Tablets include nausea, vomiting, constipation, and loss of appetite. Call your doctor about any side effect that bothers you. These are not all the side effects with Cordarone Tablets. For more information, ask your doctor or pharmacist. How should I store Cordarone Tablets? • Store Cordarone Tablets at room temperature. Protect from light. Keep Cordarone Tablets in a tightly closed container. • Safely dispose of Cordarone Tablets that are out-of-date or no longer needed. • Keep Cordarone Tablets and all medicines out of the reach of children. General information about Cordarone Tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Cordarone Tablets for a condition for which it was not prescribed. Do not share Cordarone with other people, even if they have the same symptoms that you have. It may harm them. If you have any questions or concerns about Cordarone Tablets, ask your doctor or healthcare provider. This Medication Guide summarizes the most important information about Cordarone Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Cordarone Tablets that was written for healthcare professionals. Illustration Cpu This Medication Guide may have been revised after this copy was produced. For more information and the most current Medication Guide, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Illustration Telephone What are the ingredients in Cordarone Tablets? Active Ingredient: amiodarone HCl This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-972/S-038/039 Page 31 Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rx only Manufactured for Wyeth® Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France Cordarone is a registered trademark of Sanofi-Synthelabo. Tagamet is a registered trademark of SmithKline Beecham Pharmaceuticals Co. Claritin is a registered trademark of Schering Corporation. Alavert is a registered trademark of Wyeth. ©2004, Wyeth Pharmaceuticals. All rights reserved. (Update W10427C017) (Update ET01) (Update Rev Date) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:09.747651	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018972s038s039lbl.pdf', 'application_number': 18972, 'submission_type': 'SUPPL ', 'submission_number': 38}
11,395	Cordarone® (amiodarone HCl) TABLETS Rx only DESCRIPTION Cordarone (amiodarone HCl) is a member of a new class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams' classification) effects, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2 (diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride. It is not chemically related to any other available antiarrhythmic drug. The structural formula is as follows: Structural Formula Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. CLINICAL PHARMACOLOGY Electrophysiology/Mechanisms of Action In animals, Cordarone is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of Cordarone may be due to at least two major properties: 1. a prolongation of the myocardial cell-action potential duration and refractory period and 2. noncompetitive α- and β-adrenergic inhibition. Cordarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Cordarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Cordarone as they are evidence of its pharmacological action, although Cordarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see “WARNINGS”). 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemodynamics In animal studies and after intravenous administration in man, Cordarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, Cordarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, Cordarone may have a mild negative inotropic effect. Pharmacokinetics Following oral administration in man, Cordarone is slowly and variably absorbed. The bioavailability of Cordarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of Cordarone. The effects of food upon the bioavailability of Cordarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the presence of food. Cordarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Cordarone, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral Cordarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Cordarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, Cordarone exhibited multi- compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Cordarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well- perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Cordarone should be based on individual patient requirements (see “DOSAGE AND ADMINISTRATION”). Cordarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk. Cordarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of Cordarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Cordarone is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacodynamics There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects. Monitoring Effectiveness Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: 1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of Cordarone requires some provocative approach, either exercise or programmed electrical stimulation (PES). 2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by Cordarone (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in Cordarone patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Cordarone. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment. Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While these issues remain unsettled for Cordarone, as for other agents, the prescriber of Cordarone should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of Cordarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Cordarone, the duration of follow-up, the dose of Cordarone, the use of additional antiarrhythmic agents, and many other factors. As Cordarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia- recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more. INDICATIONS AND USAGE Because of its life-threatening side effects and the substantial management difficulties associated with its use (see “WARNINGS” below), Cordarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated. 1. Recurrent ventricular fibrillation. 2. Recurrent hemodynamically unstable ventricular tachycardia. As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone Tablets favorably affects survival. Cordarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in- hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in the hospital. CONTRAINDICATIONS Cordarone is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker). 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine. WARNINGS Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur. Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life- threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mortality In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months. Cordarone therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows: Placebo Amiodarone Relative Risk N Deaths N Deaths 95%CI EMIAT 743 102 743 103 0.99 0.76-1.31 CAMIAT 596 68 606 57 0.88 0.58-1.16 These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction). Pulmonary Toxicity There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral Cordarone with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Post-marketing reports describe cases of pulmonary toxicity in patients treated with low doses of Cordarone; however, reports suggest that the use of lower loading and maintenance doses of Cordarone are associated with a decreased incidence of Cordarone-induced pulmonary toxicity. Cordarone Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Cordarone therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pulmonary toxicity secondary to Cordarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with Cordarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Cordarone therapy discontinued in these patients. Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of Cordarone induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on Cordarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of Cordarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the Cordarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with Cordarone at a lower dose has not resulted in return of toxicity. In a patient receiving Cordarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup. Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Cordarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If a diagnosis of Cordarone-induced hypersensitivity pneumonitis is made, Cordarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Cordarone discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible. Worsened Arrhythmia Cordarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (torsades de pointes [TdP]). In addition, Cordarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “Drug Interactions, Other reported interactions with amiodarone”). The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. A careful assessment of the potential risks and benefits of administering Cordarone must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients. Implantable Cardiac Devices In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed. Thyrotoxicosis Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED (see “PRECAUTIONS, Thyroid Abnormalities”). Liver Injury Elevations of hepatic enzyme levels are seen frequently in patients exposed to Cordarone and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with an elevated baseline, discontinuation of Cordarone or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with Cordarone. Loss of Vision Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of Cordarone therapy. The risks and complications of antiarrhythmic therapy with Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Cordarone. (See “ADVERSE REACTIONS”). Neonatal Hypo- or Hyperthyroidism Cordarone can cause fetal harm when administered to a pregnant woman. Although Cordarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Cordarone is used during pregnancy, or if the patient becomes pregnant while taking Cordarone, the patient should be apprised of the potential hazard to the fetus. In general, Cordarone Tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus. In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (doses compared on a body surface area basis) PRECAUTIONS Impairment of Vision Optic Neuropathy and/or Neuritis Cases of optic neuropathy and optic neuritis have been reported (see “WARNINGS”). 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see “ADVERSE REACTIONS”). Neurologic Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete. Photosensitivity Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy. Thyroid Abnormalities Cordarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal. Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by Cordarone dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue Cordarone® Tablets in some patients. Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone. The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see “WARNINGS, Thyrotoxicosis”). When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with Cordarone. In some instances hyperthyroidism was also present (see “WARNINGS” and “ADVERSE REACTIONS”). Surgery Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics. Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship of this event to Cordarone therapy is unknown. Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone. Corneal Refractive Laser Surgery Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Cordarone. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Patients Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document. Laboratory Tests Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone or discontinuing therapy. Cordarone alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid. Drug Interactions Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines (see “CLINICAL PHARMACOLOGY, Pharmacokinetics”). Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half- life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following: Protease inhibitors: Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered. Histamine H1 antagonists: Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of loratadine and amiodarone. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Histamine H2 antagonists: Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels. Antidepressants: Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of trazodone and amiodarone. Other substances: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4 mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone (see “DOSAGE AND ADMINISTRATION”). Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following: Immunosuppressives: Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. HMG-CoA reductase inhibitors: HMG-CoA reductase inhibitors that are CYP3A4 substrates (including simvastatin and atorvastatin) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis. When co-administered with amiodarone, lower starting and maintenance doses of these agents should be considered. Cardiovasculars: Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well. Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with oral amiodarone. 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose. Antihypertensives: Amiodarone should be used with caution in patients receiving β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest. Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Cordarone resulting in ineffective inhibition of platelet aggregation has been reported. Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following: 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antibiotics: Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone. Other substances, including herbal preparations: St. John's Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving amiodarone could result in reduced amiodarone levels. Other reported interactions with amiodarone: Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone. Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6. Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t½. Disopyramide increases QT prolongation which could cause arrhythmia. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “WARNINGS, Worsened Arrhythmia”.) Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil. Volatile Anesthetic Agents (See “PRECAUTIONS, Surgery, Volatile Anesthetic Agents”). In addition to the interactions noted above, chronic (>2 weeks) oral Cordarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate. Electrolyte Disturbances Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during Cordarone therapy. Use caution when coadministering Cordarone with drugs which may induce hypokalemia and/or hypomagnesemia. Carcinogenesis, Mutagenesis, Impairment of Fertility Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative. In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (dose compared on a body surface area basis) Pregnancy: Pregnancy Category D See “WARNINGS, Neonatal Hypo- or Hyperthyroidism”. Labor and Delivery It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration of gestation or on parturition. Nursing Mothers Cordarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered Cordarone have been shown to be less viable and have reduced body-weight gains. Therefore, when Cordarone therapy is indicated, the mother should be advised to discontinue nursing. Pediatric Use The safety and effectiveness of Cordarone Tablets in pediatric patients have not been established. Geriatric Use Clinical studies of Cordarone Tablets 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 Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see “WARNINGS”), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study. 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see “PRECAUTIONS”). There have been spontaneous reports of demyelinating polyneuropathy. Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses. Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See “WARNINGS”.) Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed. Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only. Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug. The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days). The following side effects were each reported in 10 to 33% of patients: Gastrointestinal: Nausea and vomiting. The following side effects were each reported in 4 to 9% of patients: Dermatologic: Solar dermatitis/photosensitivity. Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias. Gastrointestinal: Constipation, anorexia. Ophthalmologic: Visual disturbances. Hepatic: Abnormal liver-function tests. Respiratory: Pulmonary inflammation or fibrosis. 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following side effects were each reported in 1 to 3% of patients: Thyroid: Hypothyroidism, hyperthyroidism. Neurologic: Decreased libido, insomnia, headache, sleep disturbances. Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction. Gastrointestinal: Abdominal pain. Hepatic: Nonspecific hepatic disorders. Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities. The following side effects were each reported in less than 1% of patients: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities. In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism. Postmarketing Reports In postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, eczema, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis, and impotence, also have been reported with amiodarone therapy. OVERDOSAGE There have been cases, some fatal, of Cordarone overdose. In addition to general supportive measures, the patient's cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone nor its metabolite is dialyzable. The acute oral LD50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg. 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT. In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has not been determined. Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see “CLINICAL PHARMACOLOGY”). Individual patient titration is suggested according to the following guidelines: For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats. Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see “PRECAUTIONS, Drug Interactions”). Upon starting Cordarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on “Drug Interactions”). When adequate arrhythmia control is achieved, or if side effects become prominent, Cordarone dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see “CLINICAL PHARMACOLOGY–Monitoring Effectiveness”). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Cordarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see “CLINICAL PHARMACOLOGY”). 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient's arrhythmia and response to therapy. When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of Cordarone and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below: Loading Dose (Daily) Adjustment and Maintenance Dose (Daily) Ventricular Arrhythmias 1 to 3 weeks ~1 month usual maintenance 800 to 1,600 mg 600 to 800 mg 400 mg HOW SUPPLIED Cordarone® (amiodarone HCl) Tablets are available in bottles of 60 tablets as follows: 200 mg, NDC 0008-4188-04, round, convex-faced, pink tablets with a raised “C” and marked “200” on one side, with reverse side scored and marked “WYETH” and “4188.” Keep tightly closed. Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F). Protect from light. Dispense in a light-resistant, tight container. Computer Graphic This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Telephone Graphic 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide Cordarone® ′KOR-DU-RŌN Tablets (amiodarone HCl) Rx only Read the Medication Guide that comes with Cordarone Tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about Cordarone Tablets? Cordarone Tablets can cause serious side effects that can lead to death including:  lung damage  liver damage  worse heartbeat problems  thyroid problems Call your doctor or get medical help right away if you have any symptoms such as the following:  shortness of breath, wheezing, or any other trouble breathing; coughing, chest pain, or spitting up of blood  nausea or vomiting; passing brown or dark-colored urine; feel more tired than usual; your skin and whites of your eyes get yellow; or have stomach pain  heart pounding, skipping a beat, beating very fast or very slowly; feel light-headed or faint  weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor. Because of these possible side effects, Cordarone Tablets should only be used in adults with life-threatening heartbeat problems called ventricular arrhythmias, for which other treatments did not work or were not tolerated. Cordarone Tablets can cause other serious side effects. See “What are the possible or reasonably likely side effects of Cordarone Tablets?” for more information. If you get serious side effects during treatment with Cordarone Tablets you may need to stop Cordarone Tablets, have your dose changed, or get medical treatment. Talk with your doctor before you stop taking Cordarone Tablets. You may still have side effects after stopping Cordarone Tablets because the medicine stays in your body months after treatment is stopped. 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tell all your healthcare providers that you take or took Cordarone Tablets. This information is very important for other medical treatments or surgeries you may have. What are Cordarone Tablets? Cordarone is a medicine used in adults to treat life-threatening heartbeat problems called ventricular arrhythmias, for which other treatment did not work or was not tolerated. Cordarone Tablets have not been shown to help people with life-threatening heartbeat problems live longer. Treatment with Cordarone Tablets should be started in a hospital to monitor your condition. You should have regular check-ups, blood tests, chest x-rays, and eye exams before and during treatment with Cordarone Tablets to check for serious side effects. Cordarone Tablets have not been studied in children. Who should not take Cordarone Tablets? Do not take Cordarone Tablets if you:  have certain heart conditions (heart block, very slow heart rate, or slow heart rate with dizziness or lightheadedness)  have an allergy to amiodarone, iodine, or any of the other ingredients in Cordarone Tablets. See the end of this Medication Guide for a complete list of ingredients in Cordarone Tablets. What should I tell my doctor before starting Cordarone Tablets? Tell your doctor about all of your medical conditions including if you:  have lung or breathing problems  have liver problems  have or had thyroid problems  have blood pressure problems  are pregnant or planning to become pregnant. Cordarone can harm your unborn baby. Cordarone can stay in your body for months after treatment is stopped. Therefore, talk with your doctor before you plan to get pregnant.  are breastfeeding. Cordarone passes into your milk and can harm your baby. You should not breast feed while taking Cordarone. Also, Cordarone can stay in your body for months after treatment is stopped. Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Cordarone Tablets and certain other medicines can interact with each other causing serious side effects. Sometimes the dose of Cordarone Tablets or other medicines must be changed when they are used together. Especially, tell your doctor if you are taking: 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  antibiotic medicines used to treat infections  depression medicines  blood thinner medicines  HIV or AIDS medicines  cimetidine (Tagamet®), a medicine for stomach ulcers or indigestion  loratadine (for example: Claritin®, Alavert®), a medicine for allergy symptoms  seizure medicines  diabetes medicines  cyclosporine, an immunosuppressive medicine  dextromethorphan, a cough medicine  medicines for your heart, circulation, or blood pressure  water pills (diuretics)  high cholesterol or bile medicines  narcotic pain medicines  St. John's Wort Know the medicines you take. Keep a list of them with you at all times and show it to your doctor and pharmacist each time you get a new medicine. Do not take any new medicines while you are taking Cordarone Tablets unless you have talked with your doctor. How should I take Cordarone Tablets?  Take Cordarone Tablets exactly as prescribed by your doctor.  The dose of Cordarone Tablets you take has been specially chosen for you by your doctor and may change during treatment. Keep taking your medicine until your doctor tells you to stop. Do not stop taking it because you feel better. Your condition may get worse. Talk with your doctor if you have side effects.  Your doctor will tell you to take your dose of Cordarone Tablets with or without meals. Make sure you take Cordarone Tablets the same way each time.  Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach. 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Taking too many Cordarone Tablets can be dangerous. If you take too many Cordarone Tablets, call your doctor or go to the nearest hospital right away. You may need medical care right away.  If you miss a dose, do not take a double dose to make up for the dose you missed. Continue with your next regularly scheduled dose. What should I avoid while taking Cordarone Tablets?  Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach.  Avoid exposing your skin to the sun or sun lamps. Cordarone Tablets can cause a photosensitive reaction. Wear sun-block cream or protective clothing when out in the sun.  Avoid pregnancy during treatment with Cordarone Tablets. Cordarone can harm your unborn baby.  Do not breastfeed while taking Cordarone Tablets. Cordarone passes into your milk and can harm your baby. What are the possible or reasonably likely side effects of Cordarone Tablets? Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Cordarone Tablets can cause serious side effects that lead to death including lung damage, liver damage, worse heartbeat problems, and thyroid problems. See “What is the most important information I should know about Cordarone Tablets?” Some other serious side effects of Cordarone Tablets include:  vision problems that may lead to permanent blindness. You should have regular eye exams before and during treatment with Cordarone Tablets. Call your doctor if you have blurred vision, see halos, or your eyes become sensitive to light.  nerve problems. Cordarone Tablets can cause a feeling of “pins and needles” or numbness in the hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, and trouble walking.  thyroid problems. Cordarone Tablets can cause thyroid problems, including low thyroid function or overactive thyroid function. Your doctor may arrange regular blood tests to check your thyroid function during treatment with Cordarone. Call your doctor if you have weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor.  skin problems. Cordarone Tablets can cause your skin to be more sensitive to the sun or to turn a bluish-gray color. In most patients, skin color slowly returns to normal after stopping Cordarone Tablets. In some patients, skin color does not return to normal. 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other side effects of Cordarone Tablets include nausea, vomiting, constipation, and loss of appetite. Call your doctor about any side effect that bothers you. These are not all the side effects with Cordarone Tablets. For more information, ask your doctor or pharmacist. How should I store Cordarone Tablets?  Store Cordarone Tablets at room temperature. Protect from light. Keep Cordarone Tablets in a tightly closed container.  Safely dispose of Cordarone Tablets that are out-of-date or no longer needed.  Keep Cordarone Tablets and all medicines out of the reach of children. General information about Cordarone Tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Cordarone Tablets for a condition for which it was not prescribed. Do not share Cordarone with other people, even if they have the same symptoms that you have. It may harm them. If you have any questions or concerns about Cordarone Tablets, ask your doctor or healthcare provider. This Medication Guide summarizes the most important information about Cordarone Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Cordarone Tablets that was written for healthcare professionals. Computer Graphic This Medication Guide may have been revised after this copy was produced. For more information and the most current Medication Guide, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Telephone Graphic What are the ingredients in Cordarone Tablets? Active Ingredient: amiodarone HCl Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This Medication Guide has been approved by the U.S. Food and Drug Administration. Rx only Manufactured for Wyeth® Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France Cordarone is a registered trademark of Sanofi-Synthelabo. Tagamet is a registered trademark of SmithKline Beecham Pharmaceuticals Co. Claritin is a registered trademark of Schering Corporation. Alavert is a registered trademark of Wyeth. ©2004, Wyeth Pharmaceuticals. All rights reserved. W10427C020 ET01 Rev 08/09 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:09.858271	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018972s041lbl.pdf', 'application_number': 18972, 'submission_type': 'SUPPL ', 'submission_number': 41}
11,396	Cordarone® (amiodarone HCl) TABLETS Rx only DESCRIPTION Cordarone (amiodarone HCl) is a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams’ classification) effects, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone is a benzofuran derivative: 2-butyl-3 benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride. The structural formula is as follows: structural formula Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. CLINICAL PHARMACOLOGY Electrophysiology/Mechanisms of Action In animals, Cordarone is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of Cordarone may be due to at least two major properties: 1. a prolongation of the myocardial cell-action potential duration and refractory period and 2. noncompetitive α- and β-adrenergic inhibition. Cordarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Cordarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Cordarone as they are evidence of its pharmacological action, although Cordarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see “WARNINGS”). 1 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemodynamics In animal studies and after intravenous administration in man, Cordarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, Cordarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, Cordarone may have a mild negative inotropic effect. Pharmacokinetics Following oral administration in man, Cordarone is slowly and variably absorbed. The bioavailability of Cordarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of Cordarone. The effects of food upon the bioavailability of Cordarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the presence of food. Cordarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Cordarone, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA’s precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral Cordarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or Reference ID: 2876651 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Cordarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, Cordarone exhibited multi- compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Cordarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady- state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Cordarone should be based on individual patient requirements (see “DOSAGE AND ADMINISTRATION”). Cordarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk. Cordarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of Cordarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Cordarone is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence. Reference ID: 2876651 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacodynamics There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects. Monitoring Effectiveness Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: 1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of Cordarone requires some provocative approach, either exercise or programmed electrical stimulation (PES). 2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by Cordarone (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in Cordarone patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Cordarone. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment. Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). Reference ID: 2876651 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While these issues remain unsettled for Cordarone, as for other agents, the prescriber of Cordarone should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of Cordarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Cordarone, the duration of follow-up, the dose of Cordarone, the use of additional antiarrhythmic agents, and many other factors. As Cordarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia- recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more. INDICATIONS AND USAGE Because of its life-threatening side effects and the substantial management difficulties associated with its use (see “WARNINGS” below), Cordarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated. 1. Recurrent ventricular fibrillation. 2. Recurrent hemodynamically unstable ventricular tachycardia. As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone Tablets favorably affects survival. Cordarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in- hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in the hospital. CONTRAINDICATIONS Cordarone is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker). Reference ID: 2876651 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine. WARNINGS Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur. Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life- threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried. 6 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda   Mortality In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months. Cordarone therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows: Placebo Amiodarone Relative Risk N Deaths N Deaths 95%CI EMIAT 743 102 743 103 0.99 0.76-1.31 CAMIAT 596 68 606 57 0.88 0.58-1.16 These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction). Pulmonary Toxicity There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral Cordarone with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Post-marketing reports describe cases of pulmonary toxicity in patients treated with low doses of Cordarone; however, reports suggest that the use of lower loading and maintenance doses of Cordarone are associated with a decreased incidence of Cordarone-induced pulmonary toxicity. Cordarone Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Cordarone therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months. 7 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pulmonary toxicity secondary to Cordarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with Cordarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Cordarone therapy discontinued in these patients. Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of Cordarone induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on Cordarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of Cordarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the Cordarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with Cordarone at a lower dose has not resulted in return of toxicity. In a patient receiving Cordarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup. Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Cordarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary 8 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available. If a diagnosis of Cordarone-induced hypersensitivity pneumonitis is made, Cordarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Cordarone discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible. Worsened Arrhythmia Cordarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes [TdP]). In addition, Cordarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “Drug Interactions, Other reported interactions with amiodarone”). The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. A careful assessment of the potential risks and benefits of administering Cordarone must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients. Implantable Cardiac Devices In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed. Thyrotoxicosis Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED (see “PRECAUTIONS, Thyroid Abnormalities”). 9 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Liver Injury Elevations of hepatic enzyme levels are seen frequently in patients exposed to Cordarone and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Cordarone or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with Cordarone. Loss of Vision Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of Cordarone therapy. The risks and complications of antiarrhythmic therapy with Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Cordarone. (See “ADVERSE REACTIONS”). Neonatal Hypo- or Hyperthyroidism Cordarone can cause fetal harm when administered to a pregnant woman. Although Cordarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Cordarone is used during pregnancy, or if the patient becomes pregnant while taking Cordarone, the patient should be apprised of the potential hazard to the fetus. In general, Cordarone Tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus. In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (doses compared on a body surface area basis) 10 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS Impairment of Vision Optic Neuropathy and/or Neuritis Cases of optic neuropathy and optic neuritis have been reported (see “WARNINGS”). Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see “ADVERSE REACTIONS”). Neurologic Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete. Photosensitivity Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy. Thyroid Abnormalities Cordarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal. Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by Cordarone dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue Cordarone® Tablets in some patients. Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which 11 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone. The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see “WARNINGS, Thyrotoxicosis”). When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with Cordarone. In some instances hyperthyroidism was also present (see “WARNINGS” and “ADVERSE REACTIONS”). Surgery Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics. Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship of this event to Cordarone therapy is unknown. Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone. Reference ID: 2876651 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Corneal Refractive Laser Surgery Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Cordarone. Information for Patients Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document. Laboratory Tests Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone or discontinuing therapy. Cordarone alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid. Drug Interactions Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines (see “CLINICAL PHARMACOLOGY, Pharmacokinetics”). Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following: Protease inhibitors: Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered. 13 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Histamine H1 antagonists: Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and Torsade de Pointes have been reported with the co-administration of loratadine and amiodarone. Histamine H2 antagonists: Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels. Antidepressants: Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and Torsade de Pointes have been reported with the co-administration of trazodone and amiodarone. Other substances: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4 mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone (see “DOSAGE AND ADMINISTRATION”). Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following: Immunosuppressives: Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. HMG-CoA reductase inhibitors: HMG-CoA reductase inhibitors that are CYP3A4 substrates (including simvastatin and atorvastatin) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis. When co-administered with amiodarone, lower starting and maintenance doses of these agents should be considered. Cardiovasculars: Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well. 14 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with oral amiodarone. There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose. Antihypertensives: Amiodarone should be used with caution in patients receiving β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest. Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Cordarone resulting in ineffective inhibition of platelet aggregation has been reported. 15 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following: Antibiotics: Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone. Other substances, including herbal preparations: St. John’s Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving amiodarone could result in reduced amiodarone levels. Other reported interactions with amiodarone: Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone. Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6. Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t½. Disopyramide increases QT prolongation which could cause arrhythmia. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “WARNINGS, Worsened Arrhythmia”.) Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil. Volatile Anesthetic Agents (See “PRECAUTIONS, Surgery, Volatile Anesthetic Agents”). In addition to the interactions noted above, chronic (>2 weeks) oral Cordarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate. Electrolyte Disturbances Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting 16 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and during Cordarone therapy. Use caution when coadministering Cordarone with drugs which may induce hypokalemia and/or hypomagnesemia. Carcinogenesis, Mutagenesis, Impairment of Fertility Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative. In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (dose compared on a body surface area basis) Pregnancy: Pregnancy Category D See “WARNINGS, Neonatal Hypo- or Hyperthyroidism”. Labor and Delivery It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration of gestation or on parturition. Nursing Mothers Cordarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered Cordarone have been shown to be less viable and have reduced body-weight gains. Therefore, when Cordarone therapy is indicated, the mother should be advised to discontinue nursing. Pediatric Use The safety and effectiveness of Cordarone Tablets in pediatric patients have not been established. Geriatric Use Clinical studies of Cordarone Tablets 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 Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. 17 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see “WARNINGS”), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study. Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see “PRECAUTIONS”). There have been spontaneous reports of demyelinating polyneuropathy. Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses. Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See “WARNINGS”.) Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed. Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only. Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug. The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days). The following side effects were each reported in 10 to 33% of patients: Gastrointestinal: Nausea and vomiting. The following side effects were each reported in 4 to 9% of patients: Dermatologic: Solar dermatitis/photosensitivity. 18 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias. Gastrointestinal: Constipation, anorexia. Ophthalmologic: Visual disturbances. Hepatic: Abnormal liver-function tests. Respiratory: Pulmonary inflammation or fibrosis. The following side effects were each reported in 1 to 3% of patients: Thyroid: Hypothyroidism, hyperthyroidism. Neurologic: Decreased libido, insomnia, headache, sleep disturbances. Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction. Gastrointestinal: Abdominal pain. Hepatic: Nonspecific hepatic disorders. Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities. The following side effects were each reported in less than 1% of patients: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities. In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism. Postmarketing Reports In postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis, and impotence, also have been reported with amiodarone therapy. OVERDOSAGE There have been cases, some fatal, of Cordarone overdose. 19 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In addition to general supportive measures, the patient’s cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone nor its metabolite is dialyzable. The acute oral LD50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg. DOSAGE AND ADMINISTRATION BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT. In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has not been determined. Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see “CLINICAL PHARMACOLOGY”). Individual patient titration is suggested according to the following guidelines: For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats. Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see “PRECAUTIONS, Drug Interactions”). Upon starting Cordarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on “Drug Interactions”). When adequate arrhythmia control is achieved, or if side effects become prominent, Cordarone dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see “CLINICAL PHARMACOLOGY–Monitoring Effectiveness”). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Reference ID: 2876651 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda     Cordarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see “CLINICAL PHARMACOLOGY”). The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient’s arrhythmia and response to therapy. When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of Cordarone and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below: Loading Dose (Daily) Adjustment and Maintenance Dose (Daily) Ventricular Arrhythmias 1 to 3 weeks ~1 month usual maintenance 800 to 1,600 mg 600 to 800 mg 400 mg HOW SUPPLIED Cordarone® (amiodarone HCl) Tablets are available in bottles of 60 tablets as follows: 200 mg, NDC 0008-4188-04, round, convex-faced, pink tablets with a raised “C” and marked “200” on one side, with reverse side scored and marked “WYETH” and “4188.” Keep tightly closed. Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F). Protect from light. Dispense in a light-resistant, tight container. PC This product’s label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800 934-5556. telephone 21 Reference ID: 2876651 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:09.906917	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018972s042lbl.pdf', 'application_number': 18972, 'submission_type': 'SUPPL ', 'submission_number': 42}
11,397	1 Cordarone® (amiodarone HCl) TABLETS DESCRIPTION Cordarone (amiodarone HCl) is a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams’ classification) effects, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone is a benzofuran derivative: 2-butyl-3- benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride. The structural formula is as follows: Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. CLINICAL PHARMACOLOGY Electrophysiology/Mechanisms of Action In animals, Cordarone is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of Cordarone may be due to at least two major properties: 1. a prolongation of the myocardial cell-action potential duration and refractory period and 2. non-competitive antagonism of α- and β-adrenoceptors. Cordarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Cordarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Cordarone as they are evidence of its pharmacological action, although Cordarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see “WARNINGS”). Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Hemodynamics In animal studies and after intravenous administration in man, Cordarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, Cordarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, Cordarone may have a mild negative inotropic effect. Pharmacokinetics Following oral administration in man, Cordarone is slowly and variably absorbed. The bioavailability of Cordarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of Cordarone. The effects of food upon the bioavailability of Cordarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of the major metabolite of amiodarone, desethylamiodarone (DEA) increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the presence of food. Cordarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Cordarone, DEA, has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA’s precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral Cordarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is metabolized to DEA by the cytochrome P450 (CYP) enzyme group, specifically CYP3A and CYP2C8. The CYP3A isoenzyme is present in both the liver and intestines. In vitro, amiodarone and DEA, exhibit a potential to inhibit CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6 and CYP2C8. Amiodarone and DEA have also a potential to inhibit some transporters such as P- glycoprotein and organic cation transporter (OCT2). Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Cordarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, Cordarone exhibited multi- compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Cordarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady- state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Cordarone should be based on individual patient requirements (see “DOSAGE AND ADMINISTRATION”). Cordarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk. Cordarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of Cordarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Cordarone is discontinued, but the time of recurrence is variable and unpredictable. In Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence. Pharmacodynamics There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects. Monitoring Effectiveness Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: 1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of Cordarone requires some provocative approach, either exercise or programmed electrical stimulation (PES). 2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by Cordarone (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in Cordarone patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Cordarone. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). While these issues remain unsettled for Cordarone, as for other agents, the prescriber of Cordarone should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of Cordarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Cordarone, the duration of follow-up, the dose of Cordarone, the use of additional antiarrhythmic agents, and many other factors. As Cordarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia- recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more. INDICATIONS AND USAGE Because of its life-threatening side effects and the substantial management difficulties associated with its use (see “WARNINGS” below), Cordarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated. 1. Recurrent ventricular fibrillation. 2. Recurrent hemodynamically unstable ventricular tachycardia. As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone Tablets favorably affects survival. Cordarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in- hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in the hospital. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 CONTRAINDICATIONS Cordarone is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker). Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine. WARNINGS Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur. Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life- threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried. Mortality In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months. Cordarone therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows: Placebo Amiodarone Relative Risk N Deaths N Deaths 95%CI EMIAT 743 102 743 103 0.99 0.76-1.31 CAMIAT 596 68 606 57 0.88 0.58-1.16 These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction). Pulmonary Toxicity There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral Cordarone with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Postmarketing reports describe cases of pulmonary toxicity in patients treated with low doses of Cordarone; however, reports suggest that the use of lower loading and maintenance doses of Cordarone are associated with a decreased incidence of Cordarone-induced pulmonary toxicity. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Cordarone Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Cordarone therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months. Pulmonary toxicity secondary to Cordarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with Cordarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Cordarone therapy discontinued in these patients. Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of Cordarone- induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on Cordarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of Cordarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the Cordarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with Cordarone at a lower dose has not resulted in return of toxicity. In a patient receiving Cordarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Cordarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available. If a diagnosis of Cordarone-induced hypersensitivity pneumonitis is made, Cordarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone- induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Cordarone discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible. Worsened Arrhythmia Cordarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia and has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes [TdP]). In addition, Cordarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. The risk of exacerbation may be increased when other risk factors are present such as electrolytic disorders or use of concomitant antiarrhythmics or other interacting drugs (See “Drug Interactions, Other reported interactions with amiodarone”). Correct hypokalemia, hypomagnesemia or hypocalcemia whenever possible before initiating treatment with CORDARONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid- base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics and laxatives, systemic corticosteroids, amphotericin B (IV) or other drugs affecting electrolyte levels. The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Implantable Cardiac Devices In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed. Thyrotoxicosis Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED (see “PRECAUTIONS, Thyroid Abnormalities”). Liver Injury Elevations of hepatic enzyme levels are seen frequently in patients exposed to Cordarone and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Cordarone or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with Cordarone. Loss of Vision Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of Cordarone therapy. The risks and complications of antiarrhythmic therapy with Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Cordarone. (See “ADVERSE REACTIONS”). Neonatal Hypo- or Hyperthyroidism Cordarone can cause fetal harm when administered to a pregnant woman. Although Cordarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Cordarone is used during pregnancy, or if the patient becomes pregnant while taking Cordarone, the patient should be apprised of the potential hazard to the fetus. In general, Cordarone Tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus. In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose) caused abortions in greater than 90% of the animals. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (doses compared on a body surface area basis) PRECAUTIONS Impairment of Vision Optic Neuropathy and/or Neuritis Cases of optic neuropathy and optic neuritis have been reported (see “WARNINGS”). Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see “ADVERSE REACTIONS”). Neurologic Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete. Photosensitivity Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy. Thyroid Abnormalities Cordarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Hypothyroidism has been reported in 2 to 10% of patients receiving amiodarone and may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism. This condition may be identified by clinical symptoms and elevated serum TSH levels. Cases of severe hypothyroidism and myxedema coma, sometimes fatal, have been reported in association with amiodarone therapy. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the dose of or discontinuing Cordarone and considering the need for thyroid hormone supplement. Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone. The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see “WARNINGS, Thyrotoxicosis”). When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with Cordarone. In some instances hyperthyroidism was also present (see “WARNINGS” and “ADVERSE REACTIONS”). Surgery Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship of this event to Cordarone therapy is unknown. Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone. Corneal Refractive Laser Surgery Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Cordarone. Information for Patients Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document. Laboratory Tests Elevations in liver enzymes (aspartate aminotransferase and alanine aminotransferase) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone or discontinuing therapy. Cordarone alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Drug Interactions In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. Pharmacodynamic interactions Drugs inducing TdP or prolonging QT Co-administration of amiodarone with drugs known to prolong the QT interval (such as class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, IV pentamidine, and azole antifungals) increases the risk of Torsades de Points. Avoid concomitant use of drugs that prolong the QT interval. Drugs lowering heart rate or causing automaticity or conduction disorders Concomitant use of drugs with depressant effects on the sinus and AV node (e.g., digoxin, beta blockers, verapamil, diltiazem, clonidine) can potentiate the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate in patients on amiodarone and concomitant drugs that slow heart rate Pharmocokinetic interactions Effects of other medicinal products on amiodarone Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit CYP3A (e.g., certain protease inhibitors, loratadine, cimetidine, trazodone) may decrease the metabolism and increase serum concentrations of amiodarone. Concomitant use of CYP3A inducers (rifampin, St. John’s Wort), may lead to decreased serum concentrations and loss of efficacy. Consider serial measurement of amiodarone serum concentration during concomitant use of drugs affecting CYP3A activity. Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A- mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when transitioning from intravenous to oral amiodarone. Cholestyramine reduces enterohepatic circulation of amiodarone thereby increasing its elimination. This results in reduced amiodarone serum levels and half-life. Effects of amiodarone on other medicinal products Amiodarone inhibits P-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of P- glycoprotein. Reported examples of this interaction include the following: Cyclosporine (CYP3A substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 elevated creatinine, despite reduction in dose of cyclosporine. Monitor cyclosporine drug levels and renal function in patients taking both drugs. HMG-CoA reductase inhibitors: The use of HMG-CoA reductase inhibitors that are CYP3A substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs. Digoxin: In patients receiving digoxin therapy, administration of oral amiodarone results in an increase in the serum digoxin concentration. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. Antiarrhythmics: The metabolism of quinidine, procainamide, flecainide can be inhibited by amiodarone. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transition to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose. Metabolism of lidocaine (CYP3A substrate) can be inhibited by amiodarone resulting in increased lidocaine concentrations. Sinus bradycardia and seizure has been reported in patients receiving concomitant lidocaine and amiodarone. Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported. Dabigatran etexilate when taken concomitantly with amiodarone may result in elevated serum concentration of dabigatran. Fentanyl (CYP3A substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Increased steady-state levels of phenytoin during concomitant therapy with amiodarone have been reported. Monitor phenytoin levels in patients taking both drugs. Dextromethorphan is a substrate for both CYP2D6 and CYP3A. Amiodarone inhibits CYP2D6 and CYP3A. Chronic (>2 weeks) amiodarone treatment impairs metabolism of dextromethorphan leading to increased serum concentration. Carcinogenesis, Mutagenesis, Impairment of Fertility Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative. In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (dose compared on a body surface area basis) Pregnancy: Pregnancy Category D See “WARNINGS, Neonatal Hypo- or Hyperthyroidism”. Labor and Delivery It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration of gestation or on parturition. Nursing Mothers Cordarone and one of its major metabolites, DEA, are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered Cordarone have been shown to be less viable and have reduced body-weight gains. Therefore, when Cordarone therapy is indicated, the mother should be advised to discontinue nursing. Pediatric Use The safety and effectiveness of Cordarone Tablets in pediatric patients have not been established. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Geriatric Use Clinical studies of Cordarone Tablets 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 Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see “WARNINGS”), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study. Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see “PRECAUTIONS”). There have been spontaneous reports of demyelinating polyneuropathy. Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses. Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See “WARNINGS”.) Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed. Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only. Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug. The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days). The following side effects were each reported in 10 to 33% of patients: Gastrointestinal: Nausea and vomiting. The following side effects were each reported in 4 to 9% of patients: Dermatologic: Solar dermatitis/photosensitivity. Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias. Gastrointestinal: Constipation, anorexia. Ophthalmologic: Visual disturbances. Hepatic: Abnormal liver-function tests. Respiratory: Pulmonary inflammation or fibrosis. The following side effects were each reported in 1 to 3% of patients: Thyroid: Hypothyroidism, hyperthyroidism. Neurologic: Decreased libido, insomnia, headache, sleep disturbances. Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction. Gastrointestinal: Abdominal pain. Hepatic: Nonspecific hepatic disorders. Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities. The following side effects were each reported in less than 1% of patients: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities. In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism. Postmarketing Reports In postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, acute pancreatitis, renal impairment, renal insufficiency, acute renal failure, acute respiratory distress syndrome in the post-operative setting, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 alveolar hemorrhage, pleural effusion, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis, impotence and dry mouth, also have been reported with amiodarone therapy. OVERDOSAGE There have been cases, some fatal, of Cordarone overdose. In addition to general supportive measures, the patient’s cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone nor its metabolite is dialyzable. The acute oral LD50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg. DOSAGE AND ADMINISTRATION BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT. In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has not been determined. Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see “CLINICAL PHARMACOLOGY”). Individual patient titration is suggested according to the following guidelines: For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats. Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see “PRECAUTIONS, Drug Interactions”). Upon starting Cordarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on “Drug Interactions”). When adequate arrhythmia control is achieved, or if side effects become prominent, Cordarone dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see “CLINICAL PHARMACOLOGY–Monitoring Effectiveness”). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Cordarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see “CLINICAL PHARMACOLOGY”). The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient’s arrhythmia and response to therapy. When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of Cordarone and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below: Loading Dose Adjustment and Maintenance Dose (Daily) (Daily) Ventricular Arrhythmias 1 to 3 weeks ~1 month usual maintenance 800 to 1,600 mg 600 to 800 mg 400 mg HOW SUPPLIED Cordarone® (amiodarone HCl) Tablets are available in bottles of 60 tablets as follows: 200 mg, NDC 0008-4188-04, round, convex-faced, pink tablets with a raised “C” and marked “200” on one side, with reverse side scored and marked “WYETH” and “4188.” Keep tightly closed. Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F). Protect from light. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 Dispense in a light-resistant, tight container. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com . Manufactured by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France; LAB-0564-4.1 Revised March 2015 Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 MEDICATION GUIDE Cordarone® ′KOR-DU-RŌN (amiodarone HCl) What is the most important information I should know about Cordarone? Cordarone can cause serious side effects that can lead to death including:  lung problems  liver problems  worsening heartbeat problems  thyroid problems Call your doctor or get medical help right away if you have any of the following symptoms during treatment with Cordarone:  shortness of breath, wheezing, or any other trouble breathing; coughing, chest pain, or spitting up of blood  nausea or vomiting, brown or dark-colored urine feel more tired than usual, yellowing of your skin or the whites of your eyes (jaundice), or right upper stomach pain  heart pounding, skipping a beat, beating fast or slowly, feel light-headed or faint  weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor. Cordarone should only be used in people with life-threatening heartbeat problems called ventricular arrhythmias, for which other treatments did not work or were not tolerated. Cordarone can cause other serious side effects. See “What are the possible side effects of Cordarone?” If you get serious side effects during treatment you may need to stop Cordarone, have your dose changed, or get medical treatment. Talk with your doctor before you stop taking Cordarone. You may still have side effects after stopping Cordarone Tablets because the medicine stays in your body months after treatment is stopped. Tell all your healthcare providers that you take or took Cordarone Tablets. What is Cordarone? Cordarone is a prescription medicine used to treat life-threatening heartbeat problems called ventricular arrhythmias, for which other treatment did not work or was not tolerated. Cordarone has not been shown to help people with life- threatening heartbeat problems live longer. Cordarone should be started in a hospital to monitor your condition. You should have regular check-ups, blood tests, Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 chest x-rays, and eye exams before and during treatment with Cordarone to check for serious side effects. It is not known if Cordarone is safe and effective in children. Who should not take Cordarone? Do not take Cordarone if you:  have a certain heart condition called heart block with or without a slow heart rate  have a slow heart rate with dizziness or lightheadedness, and you do not have an implanted pacemaker  are allergic to amiodarone, iodine, or any of the other ingredients in Cordarone. See the end of this Medication Guide for a complete list of ingredients in Cordarone. What should I tell my doctor before taking Cordarone Before you take Cordarone tell your doctor about all of your medical conditions including if you:  have lung or breathing problems  have liver problems  have or had thyroid problems  have blood pressure problems  are pregnant or plan to become pregnant. Cordarone can harm your unborn baby. Cordarone can stay in your body for months after treatment is stopped. Talk with your doctor before you plan to get pregnant.  are breastfeeding or plan to breastfeed. Cordarone can pass into your breast milk and can harm your baby. Talk to your doctor about the best way to feed your baby. You should not breast feed while taking Cordarone. Also, Cordarone can stay in your body for months after treatment is stopped.  Tell your doctor about all the medicines you take including prescription and over-the-counter medicines, vitamins and herbal supplements. Cordarone and certain other medicines can affect (interact) with each other and cause serious side effects. You can ask your pharmacist for a list of medicines that interact with Cordarone. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take Cordarone?  Take Cordarone exactly as your doctor tells you to take it.  Your doctor will tell you how much Cordarone to take and when to take it. Cordarone can be taken with or without food. Make sure you take Cordarone the same way each time. Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24  If you take too much Cordarone, call your doctor or go to the nearest hospital emergency room right away.  If you miss a dose, wait and take your next dose at your regular time. Do not take two doses at the same. Continue with your next regularly scheduled dose. What should I avoid while taking Cordarone?  Do not drink grapefruit juice during treatment with Cordarone. Grapefruit juice affects how Cordarone is absorbed in the stomach. Avoid sunlight. Cordarone can make your skin sensitive to sun and the light from sunlamps and tanning beds. You could get severe sunburn. Use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. Talk to you doctor if you get sunburn. What are the possible side effects of Cordarone? See “What is the most important information I should know about Cordarone?”  vision problems that may lead to permanent blindness. You should have regular eye exams before and during treatment with Cordarone. Call your doctor if you have blurred vision, see halos, or your eyes become sensitive to light. Tell your doctor if you plan to have laser eye surgery.  nerve problems. Cordarone can cause a feeling of “pins and needles” or numbness in the hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, and trouble walking.  skin problems. Cordarone can cause your skin to be more sensitive to the sun or turn a bluish-gray color. In most people, skin color slowly returns to normal after stopping Cordarone. In some people, skin color does not return to normal. The most common side effects of Cordarone include:  nausea  vomiting  constipation  loss of appetite. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Cordarone. For more information, ask your doctor 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 Cordarone Tablets?  Store Cordarone at room temperature between 68°F to 77°F (20°C to 25°C). Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25  Keep Cordarone Tablets in a tightly closed container, and keep Cordaron out of the light. Keep Cordarone and all medicines out of the reach of children. General information about the safe and effective use of Cordarone Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Cordarone for a condition for which it was not prescribed. Do not give Cordarone to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Cordarone that was written for health professionals. For more information call 1-800-XXX-XXXX or go to www.pfizer.com. What are the ingredients in Cordarone Tablets? Active Ingredient: amiodarone HCl Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. This Medication Guide has been approved by the U.S. Food and Drug Administration. Cordarone is a registered trademark of Sanofi-Synthelabo. ©2004, Wyeth Pharmaceuticals. All rights reserved. Manufactured by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France LAB-0565-3.1 Revised March 2015 Reference ID: 3722432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:10.138518	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018972s047lbl.pdf', 'application_number': 18972, 'submission_type': 'SUPPL ', 'submission_number': 47}
11,399	Cordarone® (amiodarone HCl) TABLETS DESCRIPTION Cordarone (amiodarone HCl) is a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams’ classification) effects, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone is a benzofuran derivative: 2-butyl-3 benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride. The structural formula is as follows: structural formula Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. CLINICAL PHARMACOLOGY Electrophysiology/Mechanisms of Action In animals, Cordarone is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of Cordarone may be due to at least two major properties: 1. a prolongation of the myocardial cell-action potential duration and refractory period and 2. non-competitive antagonism of α- and β-adrenoceptors. Cordarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Cordarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Cordarone as they are evidence of its pharmacological action, although Cordarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see “WARNINGS”). 1 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemodynamics In animal studies and after intravenous administration in man, Cordarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, Cordarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, Cordarone may have a mild negative inotropic effect. Pharmacokinetics Following oral administration in man, Cordarone is slowly and variably absorbed. The bioavailability of Cordarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of Cordarone. The effects of food upon the bioavailability of Cordarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of the major metabolite of amiodarone, desethylamiodarone (DEA) increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the presence of food. Cordarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Cordarone, DEA, has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA’s precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral Cordarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is metabolized to DEA by the cytochrome P450 (CYP) enzyme group, specifically CYP3A and CYP2C8. The CYP3A isoenzyme is present in both the liver and intestines. In vitro, amiodarone and DEA, exhibit a potential to inhibit CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6 and CYP2C8. Amiodarone and DEA have also a potential to inhibit some transporters such as P- glycoprotein and organic cation transporter (OCT2). Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. 2 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Cordarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, Cordarone exhibited multi- compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Cordarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady- state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Cordarone should be based on individual patient requirements (see “DOSAGE AND ADMINISTRATION”). Cordarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk. Cordarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of Cordarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Cordarone is discontinued, but the time of recurrence is variable and unpredictable. In 3 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence. Pharmacodynamics There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects. Monitoring Effectiveness Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: 1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of Cordarone requires some provocative approach, either exercise or programmed electrical stimulation (PES). 2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by Cordarone (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in Cordarone patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Cordarone. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment. 4 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). While these issues remain unsettled for Cordarone, as for other agents, the prescriber of Cordarone should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of Cordarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Cordarone, the duration of follow-up, the dose of Cordarone, the use of additional antiarrhythmic agents, and many other factors. As Cordarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia- recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more. INDICATIONS AND USAGE Because of its life-threatening side effects and the substantial management difficulties associated with its use (see “WARNINGS” below), Cordarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated. 1. Recurrent ventricular fibrillation. 2. Recurrent hemodynamically unstable ventricular tachycardia. As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone Tablets favorably affects survival. Cordarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in- hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in the hospital. 5 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Cordarone is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker). Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine. WARNINGS Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur. Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life- threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need 6 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried. Mortality In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months. Cordarone therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows: Placebo Amiodarone Relative Risk N Deaths N Deaths 95%CI EMIAT 743 102 743 103 0.99 0.76-1.31 CAMIAT 596 68 606 57 0.88 0.58-1.16 These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction). Pulmonary Toxicity There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral Cordarone with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Postmarketing reports describe cases of pulmonary toxicity in patients treated with low doses of Cordarone; however, reports suggest that the use of lower loading and maintenance doses of Cordarone are associated with a decreased incidence of Cordarone-induced pulmonary toxicity. 7 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cordarone Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Cordarone therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months. Pulmonary toxicity secondary to Cordarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with Cordarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Cordarone therapy discontinued in these patients. Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of Cordarone induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on Cordarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of Cordarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the Cordarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with Cordarone at a lower dose has not resulted in return of toxicity. In a patient receiving Cordarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup. 8 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Cordarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available. If a diagnosis of Cordarone-induced hypersensitivity pneumonitis is made, Cordarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Cordarone discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible. Worsened Arrhythmia Cordarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia and has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes [TdP]). In addition, Cordarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. The risk of exacerbation may be increased when other risk factors are present such as electrolytic disorders or use of concomitant antiarrhythmics or other interacting drugs (see “Precautions, Drug Interactions”). Correct hypokalemia, hypomagnesemia or hypocalcemia whenever possible before initiating treatment with CORDARONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics and laxatives, systemic corticosteroids, amphotericin B (IV) or other drugs affecting electrolyte levels. The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. Serious Symptomatic Bradycardia When Co-administered with Ledipasvir/Sofosbuvir or with Sofosbuvir with Simeprevir Postmarketing cases of symptomatic bradycardia, some requiring pacemaker insertion and at least one fatal, have been reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir 9 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda were initiated in patients on amiodarone. Bradycardia generally occurred within hours to days, but in some cases up to 2 weeks after initiating antiviral treatment. Bradycardia generally resolved after discontinuation of antiviral treatment. The mechanism for this effect is unknown. Monitor heart rate in patients taking or recently discontinuing amiodarone when starting antiviral treatment. Implantable Cardiac Devices In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed. Thyrotoxicosis Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED (see “PRECAUTIONS, Thyroid Abnormalities”). Liver Injury Elevations of hepatic enzyme levels are seen frequently in patients exposed to Cordarone and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Cordarone or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with Cordarone. Loss of Vision Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of Cordarone therapy. The risks and complications of antiarrhythmic therapy with Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Cordarone. (see “ADVERSE REACTIONS”). Neonatal Injury Amiodarone can cause fetal harm when administered to a pregnant woman. Fetal exposure may increase the potential for adverse experiences including cardiac, thyroid, neurodevelopmental, neurological and growth effects in neonate. Inform the patient of the potential hazard to the fetus if Cordarone is administered during pregnancy or if the patient becomes pregnant while taking Cordarone. 10 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (doses compared on a body surface area basis) PRECAUTIONS Impairment of Vision Optic Neuropathy and/or Neuritis Cases of optic neuropathy and optic neuritis have been reported (see “WARNINGS”). Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see “ADVERSE REACTIONS”). Neurologic Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete. Photosensitivity Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy. Thyroid Abnormalities Cordarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid 11 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dysfunction. Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal. Hypothyroidism has been reported in 2 to 10% of patients receiving amiodarone and may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism. This condition may be identified by clinical symptoms and elevated serum TSH levels. Cases of severe hypothyroidism and myxedema coma, sometimes fatal, have been reported in association with amiodarone therapy. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the dose of or discontinuing Cordarone and considering the need for thyroid hormone supplement. Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone. The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see “WARNINGS, Thyrotoxicosis”). When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with Cordarone. In some instances hyperthyroidism was also present (see “WARNINGS” and “ADVERSE REACTIONS”). 12 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Surgery Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics. Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship of this event to Cordarone therapy is unknown. Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone. Corneal Refractive Laser Surgery Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Cordarone. Information for Patients Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document. Laboratory Tests Elevations in liver enzymes (aspartate aminotransferase and alanine aminotransferase) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone or discontinuing therapy. Cordarone alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid. 13 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. Pharmacodynamic interactions Drugs inducing TdP or prolonging QT Co-administration of amiodarone with drugs known to prolong the QT interval (such as class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, IV pentamidine, and azole antifungals) increases the risk of Torsades de Points. Avoid concomitant use of drugs that prolong the QT interval. Drugs lowering heart rate or causing automaticity or conduction disorders Concomitant use of drugs with depressant effects on the sinus and AV node (e.g., digoxin, beta blockers, verapamil, diltiazem, clonidine) can potentiate the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate in patients on amiodarone and concomitant drugs that slow heart rate. Pharmocokinetic interactions Effects of other medicinal products on amiodarone Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit CYP3A (e.g., certain protease inhibitors, loratadine, cimetidine, trazodone) may decrease the metabolism and increase serum concentrations of amiodarone. Concomitant use of CYP3A inducers (rifampin, St. John’s Wort), may lead to decreased serum concentrations and loss of efficacy. Consider serial measurement of amiodarone serum concentration during concomitant use of drugs affecting CYP3A activity. Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when transitioning from intravenous to oral amiodarone. Cholestyramine reduces enterohepatic circulation of amiodarone thereby increasing its elimination. This results in reduced amiodarone serum levels and half-life. Effects of amiodarone on other medicinal products Amiodarone inhibits P-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of P glycoprotein. Reported examples of this interaction include the following: Cyclosporine (CYP3A substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. Monitor cyclosporine drug levels and renal function in patients taking both drugs. 14 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HMG-CoA reductase inhibitors: The use of HMG-CoA reductase inhibitors that are CYP3A substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs. Digoxin: In patients receiving digoxin therapy, administration of oral amiodarone results in an increase in the serum digoxin concentration. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. Antiarrhythmics: The metabolism of quinidine, procainamide, flecainide can be inhibited by amiodarone. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transition to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose. Metabolism of lidocaine (CYP3A substrate) can be inhibited by amiodarone resulting in increased lidocaine concentrations. Sinus bradycardia and seizure has been reported in patients receiving concomitant lidocaine and amiodarone. Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported. 15 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dabigatran etexilate when taken concomitantly with amiodarone may result in elevated serum concentration of dabigatran. Fentanyl (CYP3A substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Increased steady-state levels of phenytoin during concomitant therapy with amiodarone have been reported. Monitor phenytoin levels in patients taking both drugs. Dextromethorphan is a substrate for both CYP2D6 and CYP3A. Amiodarone inhibits CYP2D6 and CYP3A. Chronic (>2 weeks) amiodarone treatment impairs metabolism of dextromethorphan leading to increased serum concentration. Carcinogenesis, Mutagenesis, Impairment of Fertility Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative. In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (dose compared on a body surface area basis) Pregnancy: See “WARNINGS, Neonatal Injury”. Teratogenic Effects Amiodarone and desethylamiodarone cross the placenta. Reported risks include: • neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles • neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure • neonatal hyperthyroxinemia • neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia. • jerk nystagmus with synchronous head titubation • fetal growth retardation • premature birth 16 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Labor and Delivery It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration of gestation or on parturition. Nursing Mothers Amiodarone and one of its major metabolites, DEA, are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have been shown to be less viable and have reduced body-weight gains. The risk of exposing the infant to amiodarone and DEA must be weighed against the potential benefit of arrhythmia suppression in the mother. Advise the mother to discontinue nursing. Pediatric Use The safety and effectiveness of Cordarone Tablets in pediatric patients have not been established. Geriatric Use Clinical studies of Cordarone Tablets 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 Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see “WARNINGS”), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study. Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see “PRECAUTIONS”). There have been spontaneous reports of demyelinating polyneuropathy. Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses. 17 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See “WARNINGS”.) Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed. Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only. Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug. The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days). The following side effects were each reported in 10 to 33% of patients: Gastrointestinal: Nausea and vomiting. The following side effects were each reported in 4 to 9% of patients: Dermatologic: Solar dermatitis/photosensitivity. Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias. Gastrointestinal: Constipation, anorexia. Ophthalmologic: Visual disturbances. Hepatic: Abnormal liver-function tests. Respiratory: Pulmonary inflammation or fibrosis. The following side effects were each reported in 1 to 3% of patients: Thyroid: Hypothyroidism, hyperthyroidism. Neurologic: Decreased libido, insomnia, headache, sleep disturbances. Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction. Gastrointestinal: Abdominal pain. Hepatic: Nonspecific hepatic disorders. Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities. The following side effects were each reported in less than 1% of patients: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities. 18 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism. Postmarketing Reports In postmarketing surveillance, serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with ledipasvir/sofosbuvir or with sofosbuvir with simeprevir, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, acute pancreatitis, renal impairment, renal insufficiency, acute renal failure, acute respiratory distress syndrome in the post-operative setting, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis, impotence and dry mouth, also have been reported with amiodarone therapy. OVERDOSAGE There have been cases, some fatal, of Cordarone overdose. In addition to general supportive measures, the patient’s cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone nor its metabolite is dialyzable. The acute oral LD50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg. DOSAGE AND ADMINISTRATION BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT. 19 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has not been determined. Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see “CLINICAL PHARMACOLOGY”). Individual patient titration is suggested according to the following guidelines: For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats. Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see “PRECAUTIONS, Drug Interactions”). Upon starting Cordarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on “Drug Interactions”). When adequate arrhythmia control is achieved, or if side effects become prominent, Cordarone dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see “CLINICAL PHARMACOLOGY–Monitoring Effectiveness”). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Cordarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see “CLINICAL PHARMACOLOGY”). The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient’s arrhythmia and response to therapy. When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of Cordarone and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below: 20 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Loading Dose (Daily) Adjustment and Maintenance Dose (Daily) Ventricular Arrhythmias 1 to 3 weeks ~1 month usual maintenance 800 to 1,600 mg 600 to 800 mg 400 mg HOW SUPPLIED Cordarone® (amiodarone HCl) Tablets are available in bottles of 60 tablets as follows: 200 mg, NDC 0008-4188-04, round, convex-faced, pink tablets with a raised “C” and marked “200” on one side, with reverse side scored and marked “WYETH” and “4188.” Keep tightly closed. Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F). Protect from light. Dispense in a light-resistant, tight container. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com . Manufactured by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France; company logo LAB-0564-5.2 Revised April 2016 21 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE Cordarone® ′KOR-DU-RŌN (amiodarone HCl) What is the most important information I should know about Cordarone? Cordarone can cause serious side effects that can lead to death including: • lung problems • liver problems • worsening heartbeat problems • thyroid problems Call your doctor or get medical help right away if you have any of the following symptoms during treatment with Cordarone: • shortness of breath, wheezing, or any other trouble breathing; coughing, chest pain, or spitting up of blood • nausea or vomiting, brown or dark-colored urine feel more tired than usual,yellowing of your skin or the whites of your eyes (jaundice), or right upper stomach pain • heart pounding, skipping a beat, beating fast or slowly, feel light-headed or faint • weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor. Cordarone should only be used in people with life-threatening heartbeat problems called ventricular arrhythmias, for which other treatments did not work or were not tolerated. Cordarone can cause other serious side effects. See “What are the possible side effects of Cordarone?” If you get serious side effects during treatment you may need to stop Cordarone, have your dose changed, or get medical treatment. Talk with your doctor before you stop taking Cordarone. You may still have side effects after stopping Cordarone Tablets because the medicine stays in your body months after treatment is stopped. Tell all your healthcare providers that you take or took Cordarone Tablets. What is Cordarone? Cordarone is a prescription medicine used to treat life-threatening heartbeat problems called ventricular arrhythmias, for which other treatment did not work or was not tolerated. Cordarone has not been shown to help people with life- threatening heartbeat problems live longer. Cordarone should be started in a hospital to monitor your condition. You should have regular check-ups, blood tests, 22 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda chest x-rays, and eye exams before and during treatment with Cordarone to check for serious side effects. It is not known if Cordarone is safe and effective in children. Who should not take Cordarone? Do not take Cordarone if you: • have a certain heart condition called heart block with or without a slow heart rate • have a slow heart rate with dizziness or lightheadedness, and you do not have an implanted pacemaker • are allergic to amiodarone, iodine, or any of the other ingredients in Cordarone. See the end of this Medication Guide for a complete list of ingredients in Cordarone. What should I tell my doctor before taking Cordarone Before you take Cordarone tell your doctor about all of your medical conditions including if you: • have lung or breathing problems • have liver problems • have or had thyroid problems • have blood pressure problems • are pregnant or plan to become pregnant. Cordarone can harm your unborn baby. Cordarone can stay in your body for months after treatment is stopped. Talk with your doctor before you plan to get pregnant. • are breastfeeding or plan to breastfeed. Cordarone can pass into your breast milk and can harm your baby. Talk to your doctor about the best way to feed your baby. You should not breast feed while taking Cordarone. Also, Cordarone can stay in your body for months after treatment is stopped. • Tell your doctor about all the medicines you take including prescription and over-the-counter medicines, vitamins and herbal supplements. Cordarone and certain other medicines can affect (interact) with each other and cause serious side effects. You can ask your pharmacist for a list of medicines that interact with Cordarone. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take Cordarone? • Take Cordarone exactly as your doctor tells you to take it. • Your doctor will tell you how much Cordarone to take and when to take it. Cordarone can be taken with or without food. Make sure you take Cordarone the same way each time. 23 Reference ID: 3921120 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 Cordarone, call your doctor or go to the nearest hospital emergency room right away. • If you miss a dose, wait and take your next dose at your regular time. Do not take two doses at the same. Continue with your next regularly scheduled dose. What should I avoid while taking Cordarone? • Do not drink grapefruit juice during treatment with Cordarone. Grapefruit juice affects how Cordarone is absorbed in the stomach. Avoid sunlight. Cordarone can make your skin sensitive to sun and the light from sunlamps and tanning beds. You could get severe sunburn. Use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. Talk to you doctor if you get sunburn. What are the possible side effects of Cordarone? See “What is the most important information I should know about Cordarone?” • vision problems that may lead to permanent blindness. You should have regular eye exams before and during treatment with Cordarone. Call your doctor if you have blurred vision, see halos, or your eyes become sensitive to light. Tell your doctor if you plan to have laser eye surgery. • nerve problems. Cordarone can cause a feeling of “pins and needles” or numbness in the hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, and trouble walking. • skin problems. Cordarone can cause your skin to be more sensitive to the sun or turn a bluish-gray color. In most people, skin color slowly returns to normal after stopping Cordarone. In some people, skin color does not return to normal. The most common side effects of Cordarone include: • nausea • constipation • vomiting • loss of appetite. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Cordarone. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 24 Reference ID: 3921120 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 Cordarone Tablets? • Store Cordarone at room temperature between 68°F to 77°F (20°C to 25°C). • Keep Cordarone Tablets in a tightly closed container, and keep Cordarone out of the light. Keep Cordarone and all medicines out of the reach of children. General information about the safe and effective use of Cordarone Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Cordarone for a condition for which it was not prescribed. Do not give Cordarone to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Cordarone that was written for health professionals. For more information call 1-800-XXX-XXXX or go to www.pfizer.com. What are the ingredients in Cordarone Tablets? Active Ingredient: amiodarone HCl Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. This Medication Guide has been approved by the U.S. Food and Drug Administration. Cordarone is a registered trademark of Sanofi-Synthelabo. ©2004, Wyeth Pharmaceuticals. All rights reserved. Manufactured by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France company logo LAB-0565-4.0 Revised March 2015 25 Reference ID: 3921120 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:10.304123	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018972s051lbl.pdf', 'application_number': 18972, 'submission_type': 'SUPPL ', 'submission_number': 51}
11,400	levatol® tablets (penbutolol sulfate) 20 mg Rx Only DESCRIPTION levatol® (penbutolol sulfate) is a synthetic ß-receptor antagonist for oral administration. The chemical name of penbutolol sulfate is (S)-1-tert-butylamino-3-(o-cyclopentylphenoxy)-2 propanol sulfate. It is provided as the levorotatory isomer. The empirical formula for penbutolol sulfate is C36H60N2O8S. Its molecular weight is 680.94. A dose of 20 mg is equivalent to 29.4 µmol. The structural formula is as follows: structural formula Penbutolol is a white, odorless, crystalline powder. levatol® is available as tablets for oral administration. Each tablet contains 20 mg of penbutolol sulfate. It also contains corn starch, D&C Yellow No. 10, lactose, magnesium stearate, povidone, silicon dioxide, talc, titanium dioxide, synthetic black iron oxide, hypromellose, simethicone and other inactive ingredients. CLINICAL PHARMACOLOGY Penbutolol is a ß-1, ß-2 (nonselective) adrenergic receptor antagonist. Experimental studies showed a dose-dependent increase in heart rate in reserpinized (norepinephrine-depleted) rats given penbutolol intravenously at doses of 0.25 to 1.0 mg/kg, suggesting that penbutolol has some intrinsic sympathomimetic activity. In human studies, however, heart rate decreases have been similar to those seen with propranolol. Penbutolol antagonizes the heart rate effects of exercise and infused isoproterenol. The ß- blocking potency of penbutolol is approximately 4 times that of propranolol. An oral dose of less than 10 mg will reduce exercise-induced tachycardia to one-half its usual level; maximum antagonism follows doses of 10 to 20 mg. The peak effect is between 1.5 and 3 hours after oral administration. The duration of effect exceeds 20 hours during a once-daily dosing regimen. During chronic administration of penbutolol, the duration of antihypertensive effects permits a once-daily dosage schedule. Acute hemodynamic effects of penbutolol have been studied following single intravenous doses between 0.1 and 4 mg. The cardiovascular responses included significant reductions in heart rate, left ventricular maximum dP/dt, cardiac output, stroke volume index, stroke work, and stroke work index. Systolic pressure and mean arterial pressure were reduced, and total peripheral resistance was increased. 1 Reference ID: 2941132 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chronic administration of penbutolol to hypertensive patients results in the hemodynamic pattern typical of ß-adrenergic blocking drugs: a reduction in cardiac index, heart rate, systolic and diastolic blood pressures, and the product of heart rate and mean arterial pressure both at rest and with all levels of exercise, without significant change in total peripheral resistance. Penbutolol causes a reduction in left ventricular contractility. Penbutolol decreases glomerular filtration rate, but not significantly. Clinical trial doses of 10 to 80 mg per day in single daily doses have reduced supine and standing systolic and diastolic blood pressures. In most studies, effects were small, generally a change in blood pressure 5 to 8/3 to 5 mm Hg greater than seen with a placebo measured 24 hours after dosing. It is not clear whether this relatively small effect reflects a characteristic of penbutolol or the particular population studied (the population had relatively mild hypertension but did not appear unusual in other respects). In a direct comparison of penbutolol with adequate doses of twice daily propranolol, no difference in blood pressure effect was seen. In a comparison of placebo and 10-, 20-, and 40-mg single daily doses of penbutolol, no significant dose-related difference was seen in response to active drug at 6 weeks, but, compared to the 10-mg dose, the two larger doses showed greater effects at 2 and 4 weeks and reached their maximum effect at 2 weeks. In several studies, dose increases from 40 to 80 mg were without additional effect on blood pressure. Response rates to penbutolol are unaffected by sex or age but are greater in caucasians than blacks. Penbutolol decreases plasma renin activity in normal subjects and in patients with essential and renovascular hypertension. The mechanisms of the antihypertensive actions of ß-receptor antagonists have not been established. However, factors that may be involved are: (1) competitive antagonism of catecholamines at peripheral adrenergic receptor sites (especially cardiac) that leads to decreased cardiac output; (2) a central nervous system (CNS) action that results in a decrease in tonic sympathetic neural outflow to the periphery; and (3) a reduction of renin secretion through blockade of ß-receptors involved in release of renin from the kidneys. Penbutolol dose dependently increases the RR and QT intervals. There is no influence on the PR, QRS, or QT c (corrected) intervals. Pharmacokinetics: Following oral administration, penbutolol is rapidly and completely absorbed. Peak plasma concentrations of penbutolol occur between 2 and 3 hours after oral administration and are proportional to single and multiple doses between 10 and 40 mg once a day. The average plasma elimination half-life of penbutolol is approximately 5 hours in normal subjects. There is no significant difference in the plasma half-life of penbutolol in healthy elderly persons or patients on renal dialysis. Twelve to 24 hours after oral administration of doses up to 120 mg, plasma concentrations of parent drug are 0% to 10% of the peak level. No accumulation of penbutolol is observed in hypertensive patients after 8 days of therapy at doses of 40 mg daily or 20 mg twice a day. Penbutolol is approximately 80% to 98% bound to plasma proteins. 2 Reference ID: 2941132 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The metabolism of penbutolol in humans involves conjugation and oxidation. The metabolites are excreted principally in the urine. When radiolabeled penbutolol was administered to humans, approximately 90% of the radioactivity was excreted in the urine. Approximately 1/6 of the dose of penbutolol was recovered as penbutolol conjugate while the remaining fraction was not identified. Conjugated penbutolol has a plasma elimination half-life of approximately 20 hours in healthy persons, 25 hours in healthy elderly persons, and 100 hours in patients on renal dialysis. Thus, accumulation of penbutolol conjugate may be expected upon multiple-dosing in renal insufficiency. An oxidative metabolite of penbutolol, 4-hydroxy penbutolol, has been identified in small quantities in plasma and urine. It is 1/8 to 1/15 times as active as the parent compound in blocking isoproterenol-induced ß-adrenergic receptor responses in isolated guinea-pig trachea and is 1/8 to 1 times as potent in anesthetized dogs. INDICATIONS AND USAGE levatol® is indicated in the treatment of mild to moderate arterial hypertension. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. CONTRAINDICATIONS levatol® is contraindicated in patients with cardiogenic shock, sinus bradycardia, second and third degree atrioventricular conduction block, bronchial asthma, and those with known hypersensitivity to this product (see WARNINGS). WARNINGS Cardiac Failure: Sympathetic stimulation may be essential for supporting circulatory function in patients with heart failure, and its inhibition by ß-adrenergic receptor blockade may precipitate more severe failure. Although ß-blockers should be avoided in overt congestive heart failure, levatol® can, if necessary, be used with caution in patients with a history of cardiac failure who are well compensated, on treatment with vasodilators, digitalis and/or diuretics. Both digitalis and penbutolol slow AV conduction. Beta-adrenergic receptor antagonists do not inhibit the inotropic action of digitalis on heart muscle. If cardiac failure persists, treatment with levatol® should be discontinued. Patients Without History of Cardiac Failure: Continued depression of the myocardium with ß-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first evidence of heart failure, patients receiving levatol® should be given appropriate treatment, and the response should be closely observed. If cardiac failure continues despite adequate intervention with appropriate drugs, levatol® should be withdrawn (gradually, if possible). Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal: Hypersensitivity to catecholamines has been observed in patients who were withdrawn from therapy with ß-blocking agents; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing levatol®, particularly in patients with ischemic heart disease, the dosage should be reduced gradually over a period of 1 to 2 weeks and the patient should be monitored carefully. If angina becomes more pronounced or acute coronary insufficiency develops, administration of levatol® should be reinstated promptly, at least on a temporary basis, and appropriate measures should be taken for the management of unstable angina. Patients should be warned against interruption or discontinuation of therapy 3 Reference ID: 2941132 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda without the physician’s advice. Because coronary artery disease is common and may not be recognized, it may not be prudent to discontinue levatol® abruptly, even in patients who are being treated only for hypertension. Nonallergic Bronchospasm (eg, chronic bronchitis,emphysema): levatol® is contraindicated in bronchial asthma. In general, patients with bronchospastic diseases should not receive ß-blockers. levatol® should be administered with caution because it may block bronchodilation produced by endogenous catecholamine stimulation of ß-2 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 Mellitus and Hypoglycemia: Beta-adrenergic receptor blockade may prevent the appearance of signs and symptoms of acute hypoglycemia, such as tachycardia and blood pressure changes. This is especially important in patients with labile diabetes. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of hypoglycemic drugs. Beta-adrenergic blockade may also impair the homeostatic response to hypoglycemia; in that event, the spontaneous recovery from hypoglycemia may be delayed during treatment with ß-adrenergic receptor antagonists. Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of ß-adrenergic receptor blockers that might precipitate a thyroid storm. PRECAUTIONS Information for Patients: Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of levatol® without the physician’s advice. Although cardiac failure rarely occurs in properly selected patients, those being treated with ß-adrenergic receptor antagonists should be advised of the symptoms of heart failure and to report such symptoms immediately, should they develop. Drug Interactions: levatol® has been used in combination with hydrochlorothiazide in at least 100 patients without unexpected adverse reactions. In one study, the combination of penbutolol and alcohol increased the number of errors in the eye-hand psychomotor function test. Penbutolol increases the volume of distribution of lidocaine in normal subjects. This could result in a requirement for higher loading doses of lidocaine. Cimetidine has no effect on the clearance of penbutolol. The major metabolite of penbutolol is a glucuronide, and it has been shown that cimetidine does not inhibit glucuronidation. Synergistic hypotensive effects, bradycardia, and arrhythmias have been reported in some patients receiving ß-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen. Reference ID: 2941132 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Generally, levatol® should not be used in patients receiving catecholamine-depleting drugs. Digoxin: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Anesthesia: Care should be taken when using anesthetic agents that depress the myocardium, such as ether, cyclopropane, and trichloroethylene, and it is prudent to use the lowest possible dose of levatol. levatol, like other ß-blockers, is a competitive inhibitor of ß-receptor agonists, and its effect on the heart can be reversed by cautious administration of such agents (eg, dobutamine or isoproterenol — see OVERDOSAGE). Manifestations of excessive vagal tone (eg, profound bradycardia, hypotension) may be corrected with atropine 1 to 3 mg IV in divided doses. Risk of Anaphylactic Reaction: While taking ß-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. Carcinogenesis, Mutagenesis, and Impairment of Fertility: There was no evidence of carcinogenicity observed in a 21-month study in mice or a 2-year study in rats. Mice were given penbutolol in the diet for 18 months at doses up to 395 mg/kg/day (about 500 times the Maximum Recommended Human Dose (MRHD) of 40 mg in a 50 kg person). Rats were given 141 mg/kg/day for the same length of time. Mice were observed for 3 months and rats for 5.5 to 7 months after termination of treatment before necropsy was performed. No evidence of mutagenic activity of penbutolol was seen in the Salmonella mutagenicity test (Ames test), the point mutation induction test (Saccharomyces), and the micronucleus test. Penbutolol had no adverse effects on fertility or general reproductive performance in mice and rats at oral doses up to 172 mg/kg/day. Pregnancy-Teratogenic Effects: Pregnancy Category C: Teratology studies in rats and rabbits revealed no teratogenic effects related to treatment with penbutolol at oral doses up to 200 mg/kg/day (250 times the MRHD). In rabbits, a slight increase in the intrauterine fetal mortality and a reduced 24-hour offspring survival rate were observed in the groups treated with 125 mg/kg/day (156 times the MRHD) but not in the groups treated with 0.2 and 5 mg (0.25 to 6 times the MRHD). There are no adequate and well-controlled studies in pregnant women. levatol® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: In a perinatal and postnatal study in rats, the pup body weight and pup survival rate were reduced at the highest dose level of 160 mg/kg/day (200 times the MRHD). 5 Reference ID: 2941132 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 levatol® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when levatol® is administered to a nursing woman. Pediatric Use: Safety and effectiveness of levatol® in pediatric patients have not been established. Geriatric Use: Clinical studies of levatol® 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 levatol® is usually well tolerated in properly selected patients. Most adverse effects observed during clinical trials have been mild and reversible. Table 1 lists the adverse reactions reported from 4 controlled studies conducted in the United States involving once-a-day administration of levatol® (at doses ranging from 10 to 120 mg) as monotherapy or in combination with hydrochlorothiazide. levatol® doses above 40 mg/day are not, however, recommended. The table includes only those events where the prevalence rate in the levatol® group was at least 1.5%, or where the reaction is of particular interest. Over a dose range from 10 to 40 mg, once a day, fatigue, nausea, and sexual impotence occurred at a greater frequency as the dose was increased. Table 1 ADVERSE REACTIONS DURING CONTROLLED US STUDIES Body System Penbutolol Placebo Propranolol Experience (N=628) (N=212) (N=266) Body as a Whole % % % Asthenia 1.6 0.9 4.9 Pain, chest 2.4 2.8 2.3 Pain, limb 2.4 1.4 1.5 Digestive System Diarrhea 3.3 1.9 2.6 Nausea 4.3 0.9 2.3 Dyspepsia 2.7 1.4 5.3 6 Reference ID: 2941132 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervous System Dizziness 4.9 2.4 4.2 Fatigue 4.4 1.9 2.6 Headache 7.8 6.1 7.5 Insomnia 1.9 0.9 2.6 Respiratory System Cough 2.1 0.5 1.1 Dyspnea 2.1 1.4 3.4 Upper respiratory 2.5 3.3 4.9 infection Skin and Appendages Sweating, excessive 1.6 0.5 2.3 Urogenital System Impotence, sexual 0.5 0.0 0.8 In a double-blind clinical trial comparing levatol® (40 mg and greater once a day) and propranolol (40 mg or more twice a day), heart rates of less than 60 beats/min. were recorded at least once in 25% of the patients in the group receiving levatol® and in 37% of the patients in the propranolol group. Corresponding figures for heart rates of less than 50 beats/min. were 1.2% and 6% respectively. No symptoms associated with bradycardia were reported. Discontinuations of levatol® because of adverse reactions have ranged between 2.4% and 6.9% of patients in double-blind, parallel, controlled clinical trials, as compared to 1.8% to 4.1% in the corresponding control groups that were given placebo. The frequency and severity of adverse reactions have not increased during long-term administration of levatol®. The prevalence of adverse reactions reported from 4 controlled clinical trials (referred to in Table 1) as reasons for discontinuation of therapy by >0.5% of the levatol® group is listed in Table 2. 7 Reference ID: 2941132 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2 DISCONTINUATIONS DURING CONTROLLED US STUDIES Body System Penbutolol Placebo Propranolol Experience (N=628) (N=212) (N=266) Body as a Whole % % % Asthenia 0.6 0.0 0.4 Pain, chest 0.6 1.4 0.4 Digestive System Nausea 0.8 0.0 0.8 Nervous System Depression 0.6 0.5 0.8 Dizziness 0.6 0.0 0.4 Fatigue 0.5 0.5 0.0 Headache 0.6 0.5 0.4 Potential Adverse Effects: In addition, certain adverse effects not listed above have been reported with other ß-blocking agents and should also be considered as potential adverse effects of levatol®. Central Nervous System: Reversible mental depression progressing to catatonia (an acute syndrome characterized by disorientation for time and place), short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance (neuropsychometrics). Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS). Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress. Hematologic: Agranulocytosis, nonthrombocytopenic and thrombocytopenic purpura. Gastrointestinal: Mesenteric arterial thrombosis and ischemic colitis. Miscellaneous: Reversible alopecia and Peyronie’s disease. The oculomucocutaneous syndrome associated with the ß-blocker practolol has not been reported with levatol® during investigational use and extensive foreign clinical experience. OVERDOSAGE There is no actual experience with levatol® overdose. The signs and symptoms that would be expected with overdosage of ß-adrenergic receptor antagonists are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. In addition to discontinuation of levatol®, gastric emptying, and close observation of the patient, the following measures might be considered as appropriate: Reference ID: 2941132 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Excessive Bradycardia: Administer atropine sulfate to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride may be administered cautiously; larger than usual doses may be needed. In refractory cases, the use of a transvenous cardiac pacemaker may be necessary. Hypotension: Sympathomimetic drug therapy, such as dopamine, dobutamine, or levarterenol, may be considered if hypotension persists despite correction of bradycardia. In refractory cases, administration of glucagon hydrochloride has been reported to be useful. Bronchospasm: A ß-2-agonist or isoproterenol hydrochloride may be administered. Additional therapy with aminophylline may be considered. Acute Cardiac Failure: Institute conventional therapy immediately. Intravenous administration of dobutamine and glucagon hydrochloride has been reported to be useful. Heart Block (Second or Third Degree): Isoproterenol hydrochloride or a transvenous cardiac pacemaker may be used. DOSAGE AND ADMINISTRATION The usual starting and maintenance dose of levatol®, used alone or in combination with other antihypertensive agents, such as thiazide-type diuretics, is 20 mg given once daily. Doses of 40 mg and 80 mg have been well-tolerated but have not been shown to give a greater antihypertensive effect. The full effect of a 20- or 40-mg dose is seen by the end of 2 weeks. A dose of 10 mg also lowers blood pressure, but the full effect is not seen for 4 to 6 weeks. HOW SUPPLIED levatol® (penbutolol sulfate) 20 mg tablets are capsule-shaped, film-coated, yellow tablets scored on both sides and imprinted in black with “SP 22” on one side. They are supplied as follows: Bottles of 100 NDC 0091-4500-15 Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. Keep tightly closed and protect from light. ANIMAL TOXICOLOGY Studies in rats indicated that the combination of penbutolol, triamterene, and hydrochlorothiazide (up to 40, 50 and 25 mg/kg respectively) increased the incidence and severity of renal tubular dilation and regeneration when compared to that in rats treated only with triamterene and hydrochlorothiazide. Dogs administered the same doses of triamterene and hydrochlorothiazide alone and in combination with penbutolol had an increase in serum alkaline phosphatase and serum alanine transferase, but there were no gross or microscopic abnormalities observed. No significant toxicologic findings were observed in rats and dogs treated with a combination of penbutolol and hydrochlorothiazide. Reference ID: 2941132 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SCHWARZ PHARMA, LLC a subsidiary of UCB, Inc. Smyrna, GA 30080 levatol® is a registered trademark of SRZ Properties, Inc. Rev. 2E 12/2010 Reference ID: 2941132 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:10.348556	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018976s012lbl.pdf', 'application_number': 18976, 'submission_type': 'SUPPL ', 'submission_number': 12}
11,401	* 10159300 barcode barcode ORTHO-NOVUM® Tablets (norethindrone/ethinyl estradiol) and MODICON® Tablets (norethindrone/ethinyl estradiol) Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. barcode barcode COMBINATION ORAL CONTRACEPTIVES Each of the following products is a combination oral contraceptive containing the prog estational compound norethindrone and the estrogenic compound ethinyl estradiol. ORTHO-NOVUM® 7/7/7 Tablets: Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include lactose, magnesium stearate and pregelatinized corn starch. Each light peach tablet contains 0.75 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as follows: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch. ORTHO-NOVUM® 1/35 Tablets: Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lac tose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as listed under green tablets in ORTHO-NOVUM 7/7/7. MODICON® Tablets: Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include lactose, magnesium stearate and prege latinized corn starch. Each green tablet contains only inert ingredients, as listed under green tablets in ORTHO-NOVUM 7/7/7. The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3 one, for ethinyl estradiol is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. Their structural formulas are as follows: chemical structure CLINICAL PHARMACOLOGY COMBINATION ORAL CONTRACEPTIVES Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). INDICATIONS AND USAGE ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON Tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contracep tion. The efficacy of these contraceptive methods, except sterilization, the IUD, and the NORPLANT® System depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. Table I: 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 Continuing Use within the First Year of Use at One Year3 Method Typical Use1 Perfect Use2 (1) (2) (3) (4) Chance4 85 85 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 20 9 56 Diaphragm7 20 6 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 Norplant-2® 0.05 0.05 88 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 con traception.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 acci dental pregnancy during the first year if they do not stop use for any other reason. 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 popula tions 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). 10However, 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-NOVUM 7/7/7, ORTHO-NOVUM 1/35 and MODICON have not been studied for and are not indicated for use in emergency contraception. CONTRAINDICATIONS Oral contraceptives should not be used in women who currently have the following conditions: • Thrombophlebitis or thromboembolic disorders • A past history of deep vein thrombophlebitis or thromboembolic disorders • Cerebral vascular or coronary artery disease (current or history) • Valvular heart disease with complications • Severe hypertension • Diabetes with vascular involvement • Headaches with focal neurological symptoms • Major surgery with prolonged immobilization • Known or suspected carcinoma of the breast • Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia • Undiagnosed abnormal genital bleeding • Cholestatic jaundice of pregnancy or jaundice with prior pill use • Acute or chronic hepatocellular disease with abnormal liver function • Hepatic adenomas or carcinomas • Known or suspected pregnancy • Hypersensitivity to any component of this product WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hyper tension, hyperlipidemias, obesity and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retro spective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with the author’s permission). For further information, the reader is referred to a text on epidemiological methods. 1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS a. Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4-10 The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute sub stantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.11 Mortality rates as sociated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives. TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE (Adapted from P.M. Layde and V. Beral, ref. #12.) Oral contraceptives may compound the effects of well-known risk factors, such as hy pertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progesto gens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral contraceptives have been shown to increase blood pressure among users (see Section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.2,3,19-24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic dis ease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.2 A two- to four-fold increase in relative risk of post-operative thromboembolic compli cations has been reported with the use of oral contraceptives.9 The relative risk of ve nous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 If feasible, oral contraceptives should be discon tinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following pro longed immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no ear lier than four weeks after delivery in women who elect not to breast feed. c. Cerebrovascular diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in gen eral, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27-29 In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contra ceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3 d. Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progesto gen in oral contraceptives and the risk of vascular disease.31-33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14-16 A decline in serum high density lipoproteins has been associated with an increased in cidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the activity of the progestogen used in the contracep tives. The activity and amount of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage reg imen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient. e. Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of develop ing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.34 10159300 ORTHO-NOVUM® Tablets (norethindrone/ethinyl estradiol) and MODICON® Tablets (norethindrone/ethinyl estradiol) Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. However, both studies were performed with oral contraceptive formulations contain ing 50 micrograms or higher of estrogens. 2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s.35 Current clin ical recommendation involves the use of lower estrogen dose formulations and a care ful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smok ing women (even with the newer low-dose formulations), there are also greater po tential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recom mended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs. TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control 15-19 20-24 25-29 30-34 35-39 40-44 and outcome No fertility 7.0 7.4 9.1 14.8 25.7 28.2 control methods* Oral contraceptives 0.3 0.5 0.9 1.9 13.8 31.6 non-smoker Oral contraceptives 2.2 3.4 6.6 13.5 51.1 117.2 smoker IUD** 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/ 1.9 1.2 1.2 1.3 2.2 2.8 spermicide* Periodic 2.5 1.6 1.6 1.7 2.9 3.6 abstinence* Deaths are birth-related Deaths are method-related Adapted from H.W. Ory, ref. #35. 3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. The risk of having breast cancer diagnosed may be slightly increased among current and re cent users of COCs. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a woman’s reproductive history or her family breast cancer history. Breast cancers diagnosed in current or previous OC users tend to be less clinically ad vanced than in nonusers. Women who currently have or have had breast cancer should not use oral contracep tives because breast cancer is usually a hormonally-sensitive tumor. 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.45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established. 4. HEPATIC NEOPLASIA Benign hepatic adenomas are associated with oral contraceptive use, although the in cidence of benign tumors is rare in the United States. Indirect calculations have esti mated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdom inal hemorrhage.50,51 Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 5. OCULAR LESIONS There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or reti nal vascular lesions. Appropriate diagnostic and therapeutic measures should be un dertaken immediately. 6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anom alies and limb reduction defects are concerned,55,56,58,59 when taken inadvertently dur ing early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed pe riod. Oral contraceptive use should be discontinued if pregnancy is confirmed. 7. GALLBLADDER DISEASE Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contracep tive users may be minimal.62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estro gens and progestogens. 8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 However, in the non-dia betic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 9. ELEVATED BLOOD PRESSURE Women with significant hypertension should not be started on hormonal contracep tion.92 An increase in blood pressure has been reported in women taking oral contra ceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity. Women with a history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant el evation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.68-71 10. HEADACHE The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause. 11. BLEEDING IRREGULARITIES Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formu lation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent. 12. ECTOPIC PREGNANCY Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. 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 good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. LIPID DISORDERS Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 4. LIVER FUNCTION If jaundice develops in any woman receiving such drugs, the medication should be dis continued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. FLUID RETENTION Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. EMOTIONAL DISORDERS Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 7. CONTACT LENSES Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 8. DRUG INTERACTIONS Changes in contraceptive effectiveness associated with co-administration of other products: Contraceptive effectiveness may be reduced when hormonal contraceptives are co administered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and bosentan. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampi cillin and tetracyclines. However, clinical pharmacology studies investigating drug in teraction between combined oral contraceptives and these antibiotics have reported inconsistent results. Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and de crease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with co administration of anti-HIV protease inhibitors. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Herbal products containing St. John’s Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the ef fectiveness of contraceptive steroids. This may also result in breakthrough bleeding. Concurrent use of bosentan and norethisterone/ethinyl estradiol may result in de creased concentrations of these contraceptive hormones thereby increasing the risk of unintended pregnancy and unscheduled bleeding. Increase in plasma levels associated with co-administered drugs: Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estra diol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Changes in plasma levels of co-administered drugs: Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been noted when these drugs were administered with oral contraceptives. Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.95 Healthcare professionals are advised to also refer to prescribing information of co-ad ministered drugs for recommendations regarding management of concomitant therapy. 9. INTERACTIONS WITH LABORATORY TESTS Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; in creased norepinephrine-induced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioim munoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 10. CARCINOGENESIS See WARNINGS Section. 11. PREGNANCY Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS Sections. 12. NURSING MOTHERS Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the post partum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combination oral contraceptives but to use other forms of contraception until she has completely weaned her child. 13. PEDIATRIC USE Safety and efficacy of ORTHO-NOVUM Tablets and MODICON Tablets has 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. 14. GERIATRIC USE This product has not been studied in women over 65 years of age and is not indicated in this population. INFORMATION FOR THE PATIENT See Patient Labeling printed below. ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (See WARNINGS Section). • Thrombophlebitis and venous thrombosis with or without embolism • Arterial thromboembolism • Pulmonary embolism • Myocardial infarction • Cerebral hemorrhage • Cerebral thrombosis • Hypertension • Gallbladder disease • Hepatic adenomas or benign liver tumors There is evidence of an association between the following conditions and the use of oral contraceptives: • Mesenteric thrombosis • Retinal thrombosis The following adverse reactions have been reported in patients receiving oral contra ceptives and are believed to be drug-related: • Nausea • Vomiting • Gastrointestinal symptoms (such as abdominal cramps and bloating) • Breakthrough bleeding • Spotting • Change in menstrual flow • Amenorrhea • Temporary infertility after discontinuation of treatment • Edema • Melasma which may persist • Breast changes: tenderness, enlargement, secretion • Change in weight (increase or decrease) • Change in cervical erosion and secretion • Diminution in lactation when given immediately postpartum • Cholestatic jaundice • Migraine • Allergic reaction, including rash, urticaria, angioedema • Mental depression • Reduced tolerance to carbohydrates • Vaginal candidiasis • Change in corneal curvature (steepening) • Intolerance to contact lenses The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted: • Pre-menstrual syndrome • Cataracts • Changes in appetite • Cystitis-like syndrome • Headache • Nervousness • Dizziness • Hirsutism • Loss of scalp hair • Erythema multiforme • Erythema nodosum • Hemorrhagic eruption • Vaginitis • Porphyria • Impaired renal function • Hemolytic uremic syndrome • Acne • Changes in libido • Colitis • Budd-Chiari Syndrome OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of combination oral contraceptives are supported by epidemiological studies which largely utilized oral con traceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estra diol or 0.05 mg mestranol.73-78 Effects on menses: • increased menstrual cycle regularity • decreased blood loss and decreased incidence of iron deficiency anemia • decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: • decreased incidence of functional ovarian cysts • decreased incidence of ectopic pregnancies Other effects: • decreased incidence of fibroadenomas and fibrocystic disease of the breast • decreased incidence of acute pelvic inflammatory disease • decreased incidence of endometrial cancer • decreased incidence of ovarian cancer DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, ORTHO-NOVUM Tablets and MODICON Tablets must be taken exactly as directed and at intervals not exceeding 24 hours. ORTHO-NOVUM Tablets and MODICON Tablets are available in the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also available. Sunday Start When taking ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON, the first “active” tablet should be taken on the first Sunday after menstruation begins. If period begins on Sunday, the first “active” tablet should be taken that day. Take one active tablet daily for 21 days followed by one green “reminder” tablet daily for 7 days. After 28 tablets have been taken, a new course is started the next day (Sunday). For the first cycle of a Sunday Start regimen, another method of contraception should be used until after the first 7 consecutive days of administration. If the patient misses one (1) “active” tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) “active” tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as condoms or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) “active” tablets in the third week or misses three (3) or more “ac tive” tablets in a row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (“How to Take the Pill” section). Day 1 Start The dosage of ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON, for the initial cycle of therapy is one “active” tablet administered daily from the 1st through the 21st day of the menstrual cycle, counting the first day of menstrual flow as “Day 1” followed by one green “reminder” tablet daily for 7 days. Tablets are taken without interruption for 28 days. After 28 tablets have been taken, a new course is started the next day. If the patient misses one (1) “active” tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) “active” tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as condoms or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) “active” tablets in the third week or misses three (3) or more “ac tive” tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (“How to Take the Pill” section). The use of ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON for contra ception may be initiated 4 weeks postpartum in women who elect not to breast feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be consid ered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic dis ease. See also PRECAUTIONS for “Nursing Mothers.”) The possibility of ovulation and conception prior to initiation of medication should be considered. (See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.) ADDITIONAL INSTRUCTIONS Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In undiag nosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnos tic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in min imizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease. Use of oral contraceptives in the event of a missed menstrual period: 1. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued if pregnancy is confirmed. 2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. HOW SUPPLIED ORTHO-NOVUM 7/7/7 Tablets are available in a DIALPAK Tablet Dispenser (NDC 0062-1781-15) containing 28 tablets, as follows: 7 white, round, flat-faced beveled edged tablets imprinted with “Ortho 535” on both sides (0.5 mg norethindrone and 0.035 mg ethinyl estradiol), 7 light peach, round, flat-faced, beveled edged tablets im printed with “Ortho 75” on both sides (0.75 mg norethindrone and 0.035 mg ethinyl estra diol), 7 peach, round, flat-faced, beveled edged tablets imprinted with “Ortho 135” on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted “Ortho” on both sides containing inert in gredients. ORTHO-NOVUM 7/7/7 is available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE Refills (NDC 0062-1781-20). ORTHO-NOVUM 1/35 Tablets are available in a DIALPAK Tablet Dispenser (NDC 0062 1761-15) containing 28 tablets, as follows: 21 peach, round, flat-faced, beveled edged tablets imprinted “Ortho 135” on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted “Ortho” on both sides containing inert ingredients. MODICON Tablets are available in a DIALPAK Tablet Dispenser (NDC 0062-1714 15) containing 28 tablets, as follows: 21 white, round, flat-faced, beveled edged tablets imprinted “Ortho 535” on both sides (0.5 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted “Ortho” on both sides containing inert ingredients. MODICON is available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE Refills (NDC 0062-1714-20). Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). REFERENCES 1. Trussel J. Contraceptive efficacy. 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The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral con traceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599. 74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800. 75. Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68-69. 76. Ory HW, Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419-422. 77. Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182-184. 78. Ory HW, Forrest JD, Lincoln R. Making choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p. 1. 79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833. 80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-control study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42. 81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the fe male genital tract. Interim results from a case-control study. Br J Cancer 1986; 54:311 317. 82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use and breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650-654. 83. Kay CR, Hannaford PC. Breast cancer and the pill – A further report from the Royal College of General Practitioners’ oral contraception study. Br J Cancer 1988; 58:675-680. 84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299. 85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am J Epidemiol 1989; 129:269-280. 86. The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973-982. 87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1-38. 88. Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral con traceptives and breast cancer: latest findings in a large cohort study. Br J Cancer 1989; 59:613-617. 89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br J Cancer 1989; 59:618-621. 90. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727. 91. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989; 130:878-882. 92. Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. 93. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294-298. 94. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113-118. 95. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo- controlled trial. Epilepsia 2007;48(3):484-489. BRIEF SUMMARY PATIENT PACKAGE INSERT Oral contraceptives, also known as “birth control pills” or “the pill,” are taken to prevent pregnancy and when taken correctly without missing any pills, have a failure rate of approximately 1% per year. The typical failure rate is approximately 5% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably in creases the chances of pregnancy. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be fatal or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: • smoke • have high blood pressure, diabetes, high cholesterol • have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice or malignant or benign liver tumors. Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy, non-smoking women (even with the newer low-dose formula tions), there are also greater potential health risks associated with pregnancy in older women. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. 2. In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleed ing. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your healthcare professional if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics may decrease oral contraceptive effectiveness. Oral contraceptives may interact with lamotrigine (LAMICTAL®), an anti convulsant used for epilepsy. This may increase the risk of seizures so your barcode healthcare professional may need to adjust the dose of lamotrigine. Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contra ceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. 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. There is insufficient evidence to rule out the possibility that the pill may cause such cancers. Taking the combination pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your healthcare pro fessional. Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. Your pharmacist should have given you the detailed patient information labeling which gives you further information which you should read and discuss with your healthcare professional. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your healthcare professional. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, in cluding some antibiotics, your pills may not work as well. Use a back-up method (such as condoms or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your health care professional about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK. The pill pack has 21 “active” pills (with hormones) to take for 3 weeks. This is followed by 1 week of green “reminder” pills (without hormones). ORTHO-NOVUM 7/7/7: There are 7 white “active” pills, 7 light peach “active” pills, 7 peach “active” pills and 7 green “reminder” pills. ORTHO-NOVUM 1/35: There are 21 peach “active” pills and 7 green “reminder” pills. MODICON: There are 21 white “active” pills and 7 green “reminder” pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up method in case you miss pills. AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON are available in the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day which will be easy to remember. SUNDAY START: ORTHO-NOVUM 7/7/7: Take the first white “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. ORTHO-NOVUM 1/35: Take the first peach “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. MODICON: Take the first white “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. Use another method of birth control such as condoms or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). DAY 1 START: ORTHO-NOVUM 7/7/7: Take the first white “active” pill of the first pack during the first 24 hours of your period. ORTHO-NOVUM 1/35: Take the first peach “active” pill of the first pack during the first 24 hours of your period. MODICON: Take the first white “active” pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: Start the next pack on the day after your last green “reminder” pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS ORTHO-NOVUM 7/7/7: If you MISS 1 white, light peach, or peach “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white or light peach “active” pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 2 peach “active” pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white, light peach, or peach “active” pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. ORTHO-NOVUM 1/35: If you MISS 1 peach “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 peach “active” pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 2 peach “active” pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE peach “active” pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. MODICON: If you MISS 1 white “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white “active” pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 2 white “active” pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OTHER INFORMATION Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare professional if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare professional, because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of combination oral contraceptives may provide certain benefits. They are: • menstrual cycles may become more regular • blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur. • pain or other symptoms during menstruation may be encountered less frequently • ectopic (tubal) pregnancy may occur less frequently • noncancerous cysts or lumps in the breast may occur less frequently • acute pelvic inflammatory disease may occur less frequently • oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your healthcare professional. They have a more technical leaflet called the Professional Labeling, which you may wish to read. The professional labeling is also published in a book entitled Physicians’ Desk Reference, available in many book stores and public libraries. If you MISS 3 OR MORE white “active” pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. A REMINDER If you forget any of the 7 green “reminder” pills in Week 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back- up method. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE “ACTIVE” PILL EACH DAY until you can reach your healthcare professional. INSTRUCTIONS FOR USE DIALPAK® Tablet Dispenser 1. The DIALPAK comes to you set up for Sunday Start. If your physician has instructed you to start pill-taking on the first SUNDAY after your menstrual period has begun, see directions in Number 3. 2. If you are to start pill-taking on a day other than SUNDAY, the enclosed calendar label has been provided and will be placed over the calendar printed on the plastic in the center of the DIALPAK. To put label in place, identify your correct starting day, lo- cate that day on the label, line that day up with the pill to which the word START and the black Day Arrow are pointing, remove the label from the backing and press the label over the printed calendar on the center plastic. 3. When the compact is open with the cover at top, the pills should be arranged as they are in the picture. If not, turn the ribbed outer ring until the pills are positioned cor- rectly. ORTHO-NOVUM 7/7/7: There are 7 white “active” pills, 7 light peach “active” pills, 7 peach “active” pills and 7 green “reminder” pills. ORTHO-NOVUM 1/35: There are 21 peach “active” pills and 7 green “reminder” pills. MODICON: There are 21 white “active” pills and 7 green “reminder” pills. 4. The first pill you will take is indicated by START and lines up with the black Day Arrow in the center of the DIALPAK. If not, see the directions in Number 3. 5. Push down on the first pill with your thumb or forefinger. The pill will come out through a hole in the back of the package. 6. The next day, turn the DIAL to the right using the ribbed outer ring to the next pill and your second pill is ready to be taken. 7. After you have taken all 21 pills, take one green “reminder” pill daily for 7 days. During this time your period should begin. 8. After you have taken all the pills, start a new pack of pills even if your period is not yet over. HOW TO INSERT REFILL (ORTHO-NOVUM 7/7/7 ONLY) 1. Lift the empty refill out of the DIALPAK. Insert the new refill by placing the black tab on refill into the opening in the ribbed outer ring of the DIALPAK (see drawing). 2. Press the refill down so that it fits firmly under the nibs. The DIAL should be turned by the ribbed outer ring so that the tablets are again arranged as in the drawing. The first white tablet will be directly over the black DAY ARROW. DETAILED PATIENT LABELING PLEASE NOTE: This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully. The following oral contraceptive products contain a combination of an estrogen and progestogen, the two kinds of female hormones: ORTHO-NOVUM® 7/7/7 Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each light peach tablet contains 0.75 mg norethindrone and 0.035 mg ethinyl estradiol. Each peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet contains inert ingredients. ORTHO-NOVUM® 1/35 Each peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet contains inert ingredients. MODICON® Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet contains inert ingredients. INTRODUCTION Any woman who considers using oral contraceptives (the birth control pill or the pill) should understand the benefits and risks of using this form of birth control. This patient labeling will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this labeling is not a replacement for a careful discussion be- tween you and your healthcare professional. You should discuss the information pro- vided in this labeling with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare professional’s advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES Oral contraceptives or “birth control pills” or “the pill” are used to prevent pregnancy and are more effective than other non-surgical methods of birth control. When they are taken correctly without missing any pills, the chance of becoming pregnant is approximately 1% (1 pregnancy per 100 women per year of use). Typical failure rates are approximately 5% per year including women who do not always take the pills exactly as directed. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other methods of birth control during the first year of use are as follows: Implant: <1% Male sterilization: <1% Injection: <1% Cervical Cap with spermicides: 20 to 40% IUD: 1 to 2% Condom alone (male): 14% Diaphragm with spermicides: 20% Condom alone (female): 21% Spermicides alone: 26% Periodic abstinence: 25% Vaginal sponge: 20 to 40% Withdrawal: 19% Female sterilization: <1% No methods: 85% WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions: • A history of heart attack or stroke • Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes • A history of blood clots in the deep veins of your legs • Chest pain (angina pectoris) • Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina • Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare professional) • Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or dur- ing previous use of the pill • Liver tumor (benign or cancerous) • Known or suspected pregnancy • Valvular heart disease with complications • Severe hypertension • Diabetes with vascular involvement • Headaches with focal neurological symptoms • If you plan to have surgery with prolonged bedrest • Hypersensitivity to any component of this product. Tell your healthcare professional if you have ever had any of these conditions. Your healthcare professional can recommend a safer method of birth control. OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES Tell your healthcare professional if you have or have had: • Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram • Diabetes • Elevated cholesterol or triglycerides • High blood pressure • Migraine or other headaches or epilepsy • Mental depression • Gallbladder, liver, heart or kidney disease • History of scanty or irregular menstrual periods Women with any of these conditions should be checked often by their healthcare professional if they choose to use oral contraceptives. Also, be sure to inform your healthcare professional if you smoke or are on any medications. RISKS OF TAKING ORAL CONTRACEPTIVES 1. Risk of developing blood clots Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a pro- longed illness or injury or have recently delivered a baby, you may be at risk of devel- oping blood clots. You should consult your healthcare professional about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contra- ceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breast feeding or four weeks after a second trimester abor- tion. If you are breast feeding, you should wait until you have weaned your child be- fore using the pill. (See also the section on Breast Feeding in General Precautions.) The risk of circulatory disease in oral contraceptive users may be higher in users of high dose pills and may be greater with longer duration of oral contraceptive use. In addition, some of these increased risks may continue for a number of years after stopping oral contraceptives. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44, it is esti- mated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a cir- culatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers. 2. Heart attacks and strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. 3. Gallbladder disease Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. Liver tumors In rare cases, 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. However, liver cancers are rare. 5. Cancer of the reproductive organs and breasts Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast ex- aminations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usu- ally a hormone-sensitive tumor. 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. There is insufficient evidence to rule out the possibility that the pill may cause such cancers. ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been cal- culated and is shown in the following table. ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control 15-19 20-24 25-29 30-34 35-39 40-44 and outcome No fertility 7.0 7.4 9.1 14.8 25.7 28.2 control methods Oral contraceptives 0.3 0.5 0.9 1.9 13.8 31.6 non-smoker Oral contraceptives 2.2 3.4 6.6 13.5 51.1 117.2 smoker IUD** 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/ 1.9 1.2 1.2 1.3 2.2 2.8 spermicide* Periodic 2.5 1.6 1.6 1.7 2.9 3.6 abstinence* Deaths are birth-related Deaths are method-related In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7-26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, al- though over the age of 40, the risk increases to 32 deaths per 100,000 women, com- pared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk asso- ciated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who do not smoke should not take oral contra- ceptives is based on information from older, higher-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of low- dose oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare professional immediately: • Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) • Pain in the calf (indicating a possible clot in the leg) • Crushing chest pain or heaviness in the chest (indicating a possible heart attack) • Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) • Sudden partial or complete loss of vision (indicating a possible clot in the eye) • Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare professional to show you how to examine your breasts) • Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) • Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) • Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fa- tigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems) Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. SIDE EFFECTS OF ORAL CONTRACEPTIVES 1. Vaginal bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleed ing which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on sched ule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your healthcare professional. 2. Contact lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your healthcare professional. 3. Fluid retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your healthcare professional. 4. Melasma A spotty darkening of the skin is possible, particularly of the face, which may persist. 5. Other side effects Other side effects may include nausea and vomiting, change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections, and al lergic reactions. If any of these side effects bother you, call your healthcare professional. GENERAL PRECAUTIONS 1. Missed periods and use of oral contraceptives before or during early pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual pe riod, continue taking your pills for the next cycle but be sure to inform your healthcare professional before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, you may be pregnant. If you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare professional immediately to determine whether you are pregnant. Do not continue to take oral con traceptives until you are sure you are not pregnant, but continue to use another method of contraception. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth de fects, but these findings have not been seen in more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your health care professional about risks to your unborn child of any medication taken during preg nancy. 2. While breast feeding If you are breast feeding, consult your healthcare professional before starting oral con traceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, combination oral contraceptives may decrease the amount and quality of your milk. If possible, do not use combination oral contracep tives while breast feeding. You should use another method of contraception since breast feeding provides only partial protection from becoming pregnant and this partial pro tection decreases significantly as you breast feed for longer periods of time. You should consider starting combination oral contraceptives only after you have weaned your child completely. 3. Laboratory tests If you are scheduled for any laboratory tests, tell your healthcare professional you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug interactions Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, pheno barbital), topiramate (TOPAMAX®), carbamazepine (Tegretol® is one brand of this drug), phenytoin (Dilantin® is one brand of this drug), phenylbutazone (Butazolidin® is one brand), certain drugs used in the treatment of HIV or AIDS, and possibly certain antibiotics. Medicine for pulmonary hypertension, such as bosentan (Tracleer®). Pregnancies and breakthrough bleeding have been reported by users of combined hormonal contra ceptives who also used some form of the herbal supplement St. John’s Wort. Hormonal contraceptives may interact with lamotrigine (LAMICTAL®), an anticonvulsant used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine. You may need to use additional contraception when you take other products which can make oral contraceptives less effective. Be sure to tell your healthcare professional if you are taking or start taking any medications while taking birth control pills. 5. Sexually transmitted diseases This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your healthcare professional. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, in cluding some antibiotics, your pills may not work as well. Use a back-up method (such as condoms or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your health care professional about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK. The pill pack has 21 “active” pills (with hormones) to take for 3 weeks. This is followed by 1 week of green “reminder” pills (without hormones). ORTHO-NOVUM 7/7/7: There are 7 white “active” pills, 7 light peach “active” pills, 7 peach “active” pills and 7 green “reminder” pills. ORTHO-NOVUM 1/35: There are 21 peach “active” pills and 7 green “reminder” pills. MODICON: There are 21 white “active” pills and 7 green “reminder” pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up method in case you miss pills. AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON are available in the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day which will be easy to remember. SUNDAY START: ORTHO-NOVUM 7/7/7: Take the first white “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. ORTHO-NOVUM 1/35: Take the first peach “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. MODICON: Take the first white “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. Use another method of birth control such as condoms or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). DAY 1 START: ORTHO-NOVUM 7/7/7: Take the first white “active” pill of the first pack during the first 24 hours of your period. ORTHO-NOVUM 1/35: Take the first peach “active” pill of the first pack during the first 24 hours of your period. MODICON: Take the first white “active” pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: Start the next pack on the day after your last green “reminder” pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS ORTHO-NOVUM 7/7/7: If you MISS 1 white, light peach, or peach “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white or light peach “active” pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 2 peach “active” pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white, light peach, or peach “active” pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. ORTHO-NOVUM 1/35: If you MISS 1 peach “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 peach “active” pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 2 peach “active” pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE peach “active” pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. MODICON: If you MISS 1 white “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white “active” pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 2 white “active” pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white “active” pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method for those 7 days. A REMINDER If you forget any of the 7 green “reminder” pills in Week 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back up method. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE “ACTIVE” PILL EACH DAY until you can reach your healthcare professional. PREGNANCY DUE TO PILL FAILURE Combination Oral Contraceptives The incidence of pill failure resulting in pregnancy is approximately one percent (i.e., one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are 5%. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contracep tives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral con traceptives by young children. Overdosage may cause nausea and withdrawal bleed ing in females. In case of overdosage, contact your healthcare professional or pharmacist. Mfd. for: Ortho Women’s Health & Urology, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, New Jersey 08869 Mfd. by: Janssen Ortho, LLC Manati, Puerto Rico 00674 © Ortho-McNeil-Janssen Pharmaceuticals, Inc. 1998 PRINTED IN U.S.A. Revised September 2008 10159300 Ortho Women's Health and Urology logo barcode This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:10.724713	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017735s107lbl.pdf', 'application_number': 18985, 'submission_type': 'SUPPL ', 'submission_number': 53}
11,398	Cordarone® (amiodarone HCl) TABLETS DESCRIPTION Cordarone (amiodarone HCl) is a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams’ classification) effects, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone is a benzofuran derivative: 2-butyl-3- benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride. The structural formula is as follows: Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. CLINICAL PHARMACOLOGY Electrophysiology/Mechanisms of Action In animals, Cordarone is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of Cordarone may be due to at least two major properties: 1. a prolongation of the myocardial cell-action potential duration and refractory period and 2. noncompetitive α- and β-adrenergic inhibition. Cordarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Cordarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Cordarone as they are evidence of its pharmacological action, although Cordarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see “WARNINGS”). 1 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemodynamics In animal studies and after intravenous administration in man, Cordarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, Cordarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, Cordarone may have a mild negative inotropic effect. Pharmacokinetics Following oral administration in man, Cordarone is slowly and variably absorbed. The bioavailability of Cordarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of Cordarone. The effects of food upon the bioavailability of Cordarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the presence of food. Cordarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Cordarone, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA’s precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral Cordarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or 2 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Cordarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, Cordarone exhibited multi- compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Cordarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady- state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Cordarone should be based on individual patient requirements (see “DOSAGE AND ADMINISTRATION”). Cordarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk. Cordarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of Cordarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Cordarone is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence. 3 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacodynamics There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects. Monitoring Effectiveness Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: 1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of Cordarone requires some provocative approach, either exercise or programmed electrical stimulation (PES). 2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by Cordarone (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in Cordarone patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Cordarone. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment. Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). 4 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While these issues remain unsettled for Cordarone, as for other agents, the prescriber of Cordarone should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of Cordarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Cordarone, the duration of follow-up, the dose of Cordarone, the use of additional antiarrhythmic agents, and many other factors. As Cordarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia- recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more. INDICATIONS AND USAGE Because of its life-threatening side effects and the substantial management difficulties associated with its use (see “WARNINGS” below), Cordarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated. 1. Recurrent ventricular fibrillation. 2. Recurrent hemodynamically unstable ventricular tachycardia. As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone Tablets favorably affects survival. Cordarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in- hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in the hospital. CONTRAINDICATIONS Cordarone is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker). 5 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine. WARNINGS Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur. Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life- threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried. 6 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda   Mortality In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months. Cordarone therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows: Placebo Amiodarone Relative Risk N Deaths N Deaths 95%CI EMIAT 743 102 743 103 0.99 0.76-1.31 CAMIAT 596 68 606 57 0.88 0.58-1.16 These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction). Pulmonary Toxicity There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral Cordarone with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Post-marketing reports describe cases of pulmonary toxicity in patients treated with low doses of Cordarone; however, reports suggest that the use of lower loading and maintenance doses of Cordarone are associated with a decreased incidence of Cordarone-induced pulmonary toxicity. Cordarone Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Cordarone therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months. 7 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pulmonary toxicity secondary to Cordarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with Cordarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Cordarone therapy discontinued in these patients. Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of Cordarone- induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on Cordarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of Cordarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the Cordarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with Cordarone at a lower dose has not resulted in return of toxicity. In a patient receiving Cordarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup. Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Cordarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary 8 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available. If a diagnosis of Cordarone-induced hypersensitivity pneumonitis is made, Cordarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone- induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Cordarone discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible. Worsened Arrhythmia Cordarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes [TdP]). In addition, Cordarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “Drug Interactions, Other reported interactions with amiodarone”). The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. A careful assessment of the potential risks and benefits of administering Cordarone must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients. Implantable Cardiac Devices In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed. Thyrotoxicosis Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED (see “PRECAUTIONS, Thyroid Abnormalities”). 9 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Liver Injury Elevations of hepatic enzyme levels are seen frequently in patients exposed to Cordarone and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Cordarone or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with Cordarone. Loss of Vision Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of Cordarone therapy. The risks and complications of antiarrhythmic therapy with Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Cordarone. (See “ADVERSE REACTIONS”). Neonatal Hypo- or Hyperthyroidism Cordarone can cause fetal harm when administered to a pregnant woman. Although Cordarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Cordarone is used during pregnancy, or if the patient becomes pregnant while taking Cordarone, the patient should be apprised of the potential hazard to the fetus. In general, Cordarone Tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus. In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (doses compared on a body surface area basis) 10 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS Impairment of Vision Optic Neuropathy and/or Neuritis Cases of optic neuropathy and optic neuritis have been reported (see “WARNINGS”). Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see “ADVERSE REACTIONS”). Neurologic Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete. Photosensitivity Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy. Thyroid Abnormalities Cordarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal. Hypothyroidism has been reported in 2 to 10% of patients receiving amiodarone and may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism. This condition may be identified by clinical symptoms and elevated serum TSH levels. Cases of severe hypothyroidism and myxedema coma, sometimes fatal, have been reported in association with amiodarone therapy. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the dose of or discontinuing Cordarone and considering the need for thyroid hormone supplement. Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone-induced 11 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone. The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see “WARNINGS, Thyrotoxicosis”). When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with Cordarone. In some instances hyperthyroidism was also present (see “WARNINGS” and “ADVERSE REACTIONS”). Surgery Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics. Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship of this event to Cordarone therapy is unknown. Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone. 12 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Corneal Refractive Laser Surgery Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Cordarone. Information for Patients Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document. Laboratory Tests Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone or discontinuing therapy. Cordarone alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid. Drug Interactions Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines (see “CLINICAL PHARMACOLOGY, Pharmacokinetics”). Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following: Protease inhibitors: Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered. 13 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Histamine H1 antagonists: Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and Torsade de Pointes have been reported with the co-administration of loratadine and amiodarone. Histamine H2 antagonists: Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels. Antidepressants: Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and Torsade de Pointes have been reported with the co-administration of trazodone and amiodarone. Other substances: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4- mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone (see “DOSAGE AND ADMINISTRATION”). Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following: Immunosuppressives: Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. HMG-CoA reductase inhibitors: The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs. Cardiovasculars: Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely 14 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well. Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with oral amiodarone. There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose. Antihypertensives: Amiodarone should be used with caution in patients receiving β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest. Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. 15 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Cordarone resulting in ineffective inhibition of platelet aggregation has been reported. Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following: Antibiotics: Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone. Other substances, including herbal preparations: St. John’s Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving amiodarone could result in reduced amiodarone levels. Other reported interactions with amiodarone: Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone. Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6. Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t½. Disopyramide increases QT prolongation which could cause arrhythmia. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See “WARNINGS, Worsened Arrhythmia”.) Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil. Volatile Anesthetic Agents (See “PRECAUTIONS, Surgery, Volatile Anesthetic Agents”). In addition to the interactions noted above, chronic (>2 weeks) oral Cordarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate. 16 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Electrolyte Disturbances Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during Cordarone therapy. Use caution when coadministering Cordarone with drugs which may induce hypokalemia and/or hypomagnesemia. Carcinogenesis, Mutagenesis, Impairment of Fertility Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative. In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose). 600 mg in a 50 kg patient (dose compared on a body surface area basis) Pregnancy: Pregnancy Category D See “WARNINGS, Neonatal Hypo- or Hyperthyroidism”. Labor and Delivery It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration of gestation or on parturition. Nursing Mothers Cordarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered Cordarone have been shown to be less viable and have reduced body-weight gains. Therefore, when Cordarone therapy is indicated, the mother should be advised to discontinue nursing. Pediatric Use The safety and effectiveness of Cordarone Tablets in pediatric patients have not been established. Geriatric Use Clinical studies of Cordarone Tablets 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. 17 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see “WARNINGS”), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study. Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see “PRECAUTIONS”). There have been spontaneous reports of demyelinating polyneuropathy. Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses. Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See “WARNINGS”.) Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed. Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only. Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug. The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days). The following side effects were each reported in 10 to 33% of patients: Gastrointestinal: Nausea and vomiting. 18 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following side effects were each reported in 4 to 9% of patients: Dermatologic: Solar dermatitis/photosensitivity. Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias. Gastrointestinal: Constipation, anorexia. Ophthalmologic: Visual disturbances. Hepatic: Abnormal liver-function tests. Respiratory: Pulmonary inflammation or fibrosis. The following side effects were each reported in 1 to 3% of patients: Thyroid: Hypothyroidism, hyperthyroidism. Neurologic: Decreased libido, insomnia, headache, sleep disturbances. Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction. Gastrointestinal: Abdominal pain. Hepatic: Nonspecific hepatic disorders. Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities. The following side effects were each reported in less than 1% of patients: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities. In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism. Postmarketing Reports In postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, acute pancreatitis, renal impairment, renal insufficiency, acute renal failure, acute respiratory distress syndrome in the post-operative setting, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis, impotence and dry mouth, also have been reported with amiodarone therapy. 19 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE There have been cases, some fatal, of Cordarone overdose. In addition to general supportive measures, the patient’s cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone nor its metabolite is dialyzable. The acute oral LD50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg. DOSAGE AND ADMINISTRATION BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE- THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT. In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has not been determined. Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see “CLINICAL PHARMACOLOGY”). Individual patient titration is suggested according to the following guidelines: For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats. Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see “PRECAUTIONS, Drug Interactions”). Upon starting Cordarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on “Drug Interactions”). When adequate arrhythmia control is achieved, or if side effects become prominent, Cordarone dose should be reduced to 20 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda   sp; 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see “CLINICAL PHARMACOLOGY–Monitoring Effectiveness”). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Cordarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see “CLINICAL PHARMACOLOGY”). The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient’s arrhythmia and response to therapy. When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of Cordarone and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below: Loading Dose (Daily) Adjustment and Maintenance Dose (Daily) Ventricular Arrhythmias 1 to 3 weeks ~1 month usual maintenance 800 to 1,600 mg 600 to 800 mg 400 mg HOW SUPPLIED Cordarone® (amiodarone HCl) Tablets are available in bottles of 60 tablets as follows: 200 mg, NDC 0008-4188-04, round, convex-faced, pink tablets with a raised “C” and marked “200” on one side, with reverse side scored and marked “WYETH” and “4188.” Keep tightly closed. Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F). Protect from light. Dispense in a light-resistant, tight container. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com. Manufactured by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France 21 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LAB-0564-3.0 Revised December 2014 Reference ID: 3676851 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide Cordarone® ′KOR-DU-RŌN Tablets (amiodarone HCl) Read the Medication Guide that comes with Cordarone Tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about Cordarone Tablets? Cordarone Tablets can cause serious side effects that can lead to death including: • lung damage • liver damage • worse heartbeat problems • thyroid problems Call your doctor or get medical help right away if you have any symptoms such as the following: • shortness of breath, wheezing, or any other trouble breathing; coughing, chest pain, or spitting up of blood • nausea or vomiting; passing brown or dark-colored urine; feel more tired than usual; your skin and whites of your eyes get yellow; or have stomach pain • heart pounding, skipping a beat, beating very fast or very slowly; feel light-headed or faint • weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor. Because of these possible side effects, Cordarone Tablets should only be used in adults with life-threatening heartbeat problems called ventricular arrhythmias, for which other treatments did not work or were not tolerated. Cordarone Tablets can cause other serious side effects. See “What are the possible or reasonably likely side effects of Cordarone Tablets?” for more information. If you get serious side effects during treatment with Cordarone Tablets you may need to stop Cordarone Tablets, have your dose changed, or get medical treatment. Talk with your doctor before you stop taking Cordarone Tablets. You may still have side effects after stopping Cordarone Tablets because the medicine stays in your body months after treatment is stopped. Tell all your healthcare providers that you take or took Cordarone Tablets. This information is very important for other medical treatments or surgeries you may have. 23 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What are Cordarone Tablets? Cordarone is a medicine used in adults to treat life-threatening heartbeat problems called ventricular arrhythmias, for which other treatment did not work or was not tolerated. Cordarone Tablets have not been shown to help people with life-threatening heartbeat problems live longer. Treatment with Cordarone Tablets should be started in a hospital to monitor your condition. You should have regular check-ups, blood tests, chest x-rays, and eye exams before and during treatment with Cordarone Tablets to check for serious side effects. Cordarone Tablets have not been studied in children. Who should not take Cordarone Tablets? Do not take Cordarone Tablets if you: • have certain heart conditions (heart block, very slow heart rate, or slow heart rate with dizziness or lightheadedness) • have an allergy to amiodarone, iodine, or any of the other ingredients in Cordarone Tablets. See the end of this Medication Guide for a complete list of ingredients in Cordarone Tablets. What should I tell my doctor before starting Cordarone Tablets? Tell your doctor about all of your medical conditions including if you: • have lung or breathing problems • have liver problems • have or had thyroid problems • have blood pressure problems • are pregnant or planning to become pregnant. Cordarone can harm your unborn baby. Cordarone can stay in your body for months after treatment is stopped. Therefore, talk with your doctor before you plan to get pregnant. • are breastfeeding. Cordarone passes into your milk and can harm your baby. You should not breast feed while taking Cordarone. Also, Cordarone can stay in your body for months after treatment is stopped. Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Cordarone Tablets and certain other medicines can interact with each other causing serious side effects. Sometimes the dose of Cordarone Tablets or other medicines must be changed when they are used together. Especially, tell your doctor if you are taking: • antibiotic medicines used to treat infections • depression medicines • blood thinner medicines • HIV or AIDS medicines • cimetidine (Tagamet®), a medicine for stomach ulcers or indigestion • loratadine (for example: Claritin®, Alavert®), a medicine for allergy symptoms 24 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • seizure medicines • diabetes medicines • cyclosporine, an immunosuppressive medicine • dextromethorphan, a cough medicine • medicines for your heart, circulation, or blood pressure • water pills (diuretics) • high cholesterol or bile medicines • narcotic pain medicines • St. John’s Wort Know the medicines you take. Keep a list of them with you at all times and show it to your doctor and pharmacist each time you get a new medicine. Do not take any new medicines while you are taking Cordarone Tablets unless you have talked with your doctor. How should I take Cordarone Tablets? • Take Cordarone Tablets exactly as prescribed by your doctor. • The dose of Cordarone Tablets you take has been specially chosen for you by your doctor and may change during treatment. Keep taking your medicine until your doctor tells you to stop. Do not stop taking it because you feel better. Your condition may get worse. Talk with your doctor if you have side effects. • Your doctor will tell you to take your dose of Cordarone Tablets with or without meals. Make sure you take Cordarone Tablets the same way each time. • Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach. • Taking too many Cordarone Tablets can be dangerous. If you take too many Cordarone Tablets, call your doctor or go to the nearest hospital right away. You may need medical care right away. • If you miss a dose, do not take a double dose to make up for the dose you missed. Continue with your next regularly scheduled dose. What should I avoid while taking Cordarone Tablets? • Do not drink grapefruit juice during treatment with Cordarone Tablets. Grapefruit juice affects how Cordarone is absorbed in the stomach. • Avoid exposing your skin to the sun or sun lamps. Cordarone Tablets can cause a photosensitive reaction. Wear sun-block cream or protective clothing when out in the sun. • Avoid pregnancy during treatment with Cordarone Tablets. Cordarone can harm your unborn baby. • Do not breastfeed while taking Cordarone Tablets. Cordarone passes into your milk and can harm your baby. What are the possible or reasonably likely side effects of Cordarone Tablets? Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 25 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cordarone Tablets can cause serious side effects that lead to death including lung damage, liver damage, worse heartbeat problems, and thyroid problems. See “What is the most important information I should know about Cordarone Tablets?” Some other serious side effects of Cordarone Tablets include: • vision problems that may lead to permanent blindness. You should have regular eye exams before and during treatment with Cordarone Tablets. Call your doctor if you have blurred vision, see halos, or your eyes become sensitive to light. • nerve problems. Cordarone Tablets can cause a feeling of “pins and needles” or numbness in the hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, and trouble walking. • thyroid problems. Cordarone Tablets can cause thyroid problems, including low thyroid function or overactive thyroid function. Your doctor may arrange regular blood tests to check your thyroid function during treatment with Cordarone. Call your doctor if you have weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor. • skin problems. Cordarone Tablets can cause your skin to be more sensitive to the sun or to turn a bluish-gray color. In most patients, skin color slowly returns to normal after stopping Cordarone Tablets. In some patients, skin color does not return to normal. Other side effects of Cordarone Tablets include nausea, vomiting, constipation, and loss of appetite. Call your doctor about any side effect that bothers you. These are not all the side effects with Cordarone Tablets. For more information, ask your doctor or pharmacist. How should I store Cordarone Tablets? • Store Cordarone Tablets at room temperature. Protect from light. Keep Cordarone Tablets in a tightly closed container. • Safely dispose of Cordarone Tablets that are out-of-date or no longer needed. • Keep Cordarone Tablets and all medicines out of the reach of children. General information about Cordarone Tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Cordarone Tablets for a condition for which it was not prescribed. Do not share Cordarone with other people, even if they have the same symptoms that you have. It may harm them. If you have any questions or concerns about Cordarone Tablets, ask your doctor or healthcare provider. This Medication Guide summarizes the most important information about Cordarone Tablets. If you would like more information, talk with your doctor. You can ask your doctor or 26 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pharmacist for information about Cordarone Tablets that was written for healthcare professionals. This product’s Medication Guide may have been updated. For current Medication Guide, please visit www.pfizer.com. What are the ingredients in Cordarone Tablets? Active Ingredient: amiodarone HCl Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. This Medication Guide has been approved by the U.S. Food and Drug Administration. Cordarone is a registered trademark of Sanofi-Synthelabo. Tagamet is a registered trademark of SmithKline Beecham Pharmaceuticals Co. Claritin is a registered trademark of Schering Corporation. Alavert is a registered trademark of Wyeth. ©2004, Wyeth Pharmaceuticals. All rights reserved. Manufactured by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France LAB-0565-1.0 Revised October 2011 27 Reference ID: 3676851 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:10.847563	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018972s050lbl.pdf', 'application_number': 18972, 'submission_type': 'SUPPL ', 'submission_number': 50}
11,402	1 ORTHO-NOVUM® Tablets (norethindrone/ethinyl estradiol) and MODICON® Tablets (norethindrone/ethinyl estradiol) WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including ORTHO-NOVUM and MODICON, should not be used by women who are over 35 years of age and smoke. Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. COMBINED ORAL CONTRACEPTIVES Each of the following products is a combined oral contraceptive containing the progestational compound norethindrone and the estrogenic compound ethinyl estradiol. ORTHO-NOVUM® 7/7/7 Tablets: Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include lactose, magnesium stearate and pregelatinized corn starch. Each light peach tablet contains 0.75 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as follows: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch. ORTHO-NOVUM® 1/35 Tablets: Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as listed under green tablets in ORTHO-NOVUM® 7/7/7. MODICON® Tablets: Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as listed under green tablets in ORTHO-NOVUM® 7/7/7. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one, and for ethinyl estradiol is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. Their structural formulas are as follows: Norethindrone Ethinyl estradiol CLINICAL PHARMACOLOGY Combined Oral Contraceptives Combined oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). INDICATIONS AND USAGE ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® Tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy rates for users of combined oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the NORPLANT® System depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. 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 Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year* Method (1) Typical Use† (2) Perfect Use‡ (3) (4) Chance# 85 85 SpermicidesÞ 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermalß 2 Post-Ovulation 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 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 Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year* Method (1) Typical Use† (2) Perfect Use‡ (3) (4) Capà Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragmà 20 6 56 Withdrawal 19 4 Condomè 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 Norplant-2® 0.05 0.05 88 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%.§ Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.¶ 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. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 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 Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year* Method (1) Typical Use† (2) Perfect Use‡ (3) (4) * Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. † 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. ‡ 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. § 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). ¶ 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. # 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. Þ Foams, creams, gels, vaginal suppositories, and vaginal film. ß Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. à With spermicidal cream or jelly. è Without spermicides. ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35 and MODICON® have not been studied for and are not indicated for use in emergency contraception. CONTRAINDICATIONS Oral contraceptives should not be used in women who currently have the following conditions: • Thrombophlebitis or thromboembolic disorders • A past history of deep vein thrombophlebitis or thromboembolic disorders • Known thrombophilic conditions • Cerebral vascular or coronary artery disease (current or history) • Valvular heart disease with complications • Persistent blood pressure values of ≥ 160 mm Hg systolic or ≥ 100 mg Hg diastolic96 • Diabetes with vascular involvement This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 • Headaches with focal neurological symptoms • Major surgery with prolonged immobilization • Known or suspected carcinoma of the breast • Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia • Undiagnosed abnormal genital bleeding • Cholestatic jaundice of pregnancy or jaundice with prior pill use • Acute or chronic hepatocellular disease with abnormal liver function • Hepatic adenomas or carcinomas • Known or suspected pregnancy • Hypersensitivity to any component of this product WARNINGS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including ORTHO-NOVUM and MODICON, should not be used by women who are over 35 years of age and smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with the author’s permission). For further information, the reader is referred to a text on epidemiological methods. 1. Thromboembolic Disorders and Other Vascular Problems a. Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4–10 The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older, and in nonsmokers over the age of 40 among women who use oral contraceptives. (See Figure 1). Figure 1. Circulatory Disease Mortality Rates per 100,000 Women-Years by Age, Smoking Status and Oral Contraceptive Use (Adapted from P.M. Layde and V. Beral, ref. #12.) Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14–18 Oral contraceptives have been shown to increase blood pressure among users (see Section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.2,3,19–24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives gradually disappears after combined oral contraceptive (COC) use is stopped.2 VTE risk is highest in the first year of use and when restarting hormonal contraception after a break of four weeks or longer. A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed. c. Cerebrovascular diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27–29 In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3 d. Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.31–33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14–16 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the activity of the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 progestogen used in the contraceptives. The activity and amount of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient. e. Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40–49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.34 However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens. 2. Estimates of Mortality From Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 2). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s.35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs. Table 2: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15–19 20–24 25–29 30–34 35–39 40–44 No fertility-control methods* 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker† 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker† 2.2 3.4 6.6 13.5 51.1 117.2 IUD† 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 Adapted from H.W. Ory, ref. #35. * Deaths are birth-related. † Deaths are method-related. 3. Carcinoma of the Reproductive Organs and Breasts Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a woman’s reproductive history or her family breast cancer history. Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in nonusers. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor. 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.45–48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 4. Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50,51 Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 5. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 6. Oral Contraceptive Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned,55,56,58,59 when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. 7. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.62–64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 8. Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 9. Elevated Blood Pressure Women with significant hypertension should not be started on hormonal contraception.92 An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity. Women with a history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If these women elect to use oral contraceptives, they should be monitored closely and if a clinically significant persistent elevation of blood pressure (BP) occurs (≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic) and cannot be adequately controlled, oral contraceptives should be discontinued. In general, women who develop hypertension during hormonal contraceptive therapy should be switched to a non-hormonal contraceptive. If other contraceptive methods are not suitable, hormonal contraceptive therapy may continue combined with antihypertensive therapy. Regular monitoring of BP throughout hormonal contraceptive therapy is recommended.96 For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.68–71 10. Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause. 11. Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent. 12. Ectopic Pregnancy Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. 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 good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. Lipid Disorders Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 4. Liver Function If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. Fluid Retention Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. Emotional Disorders Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 7. Contact Lenses Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 8. Drug Interactions Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Effects of Other Drugs on Combined Hormonal Contraceptives Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with CHCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the plasma concentrations of COCs Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). Colesevelam: Colesevelam, a bile acid sequestrant, given together with a combination oral hormonal contraceptive, has been shown to significantly decrease the AUC of EE. A drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. Effects of Combined Hormonal Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increases with use of COCs. 9. Interactions with Laboratory Tests Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 10. Carcinogenesis See WARNINGS. 11. Pregnancy Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS. 12. Nursing Mothers Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combined oral contraceptives given in the postpartum period may This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combined oral contraceptives but to use other forms of contraception until she has completely weaned her child. 13. Pediatric Use Safety and efficacy of ORTHO-NOVUM® Tablets and MODICON® 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. 14. Geriatric Use This product has not been studied in women over 65 years of age and is not indicated in this population. INFORMATION FOR THE PATIENT See Patient Labeling printed below. ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (See WARNINGS). • Thrombophlebitis and venous thrombosis with or without embolism • Arterial thromboembolism • Pulmonary embolism • Myocardial infarction • Cerebral hemorrhage • Cerebral thrombosis • Hypertension • Gallbladder disease • Hepatic adenomas or benign liver tumors There is evidence of an association between the following conditions and the use of oral contraceptives: • Mesenteric thrombosis • Retinal thrombosis The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: • Nausea This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 • Vomiting • Gastrointestinal symptoms (such as abdominal cramps and bloating) • Breakthrough bleeding • Spotting • Change in menstrual flow • Amenorrhea • Temporary infertility after discontinuation of treatment • Edema • Melasma which may persist • Breast changes: tenderness, enlargement, secretion • Change in weight (increase or decrease) • Change in cervical erosion and secretion • Diminution in lactation when given immediately postpartum • Cholestatic jaundice • Migraine • Allergic reaction, including rash, urticaria, angioedema • Mental depression • Reduced tolerance to carbohydrates • Vaginal candidiasis • Change in corneal curvature (steepening) • Intolerance to contact lenses The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted: • Pre-menstrual syndrome • Cataracts • Changes in appetite • Cystitis-like syndrome • Headache • Nervousness • Dizziness • Hirsutism This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 • Loss of scalp hair • Erythema multiforme • Erythema nodosum • Hemorrhagic eruption • Vaginitis • Porphyria • Impaired renal function • Hemolytic uremic syndrome • Acne • Changes in libido • Colitis • Budd-Chiari Syndrome The following adverse reactions were also reported in clinical trials or during post-marketing experience: Gastrointestinal Disorders: diarrhea, pancreatitis; Musculoskeletal and Connective Tissue Disorders: muscle spasms, back pain; Reproductive System and Breast Disorders vulvovaginal pruritus, pelvic pain, dysmenorrhea, vulvovaginal dryness; Psychiatric Disorders: anxiety, mood swings, mood altered; Skin and Subcutaneous Tissue Disorders: pruritus, photosensitivity reaction; General Disorders and Administration Site Conditions: edema peripheral, fatigue, irritability, asthenia, malaise; Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): breast cancer, breast mass, breast neoplasm, cervix carcinoma; Immune System Disorders: anaphylactic/anaphylactoid reaction; Hepatobiliary Disorders: hepatitis, cholelithiasis. OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of combined oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol.73–78 Effects on menses: • increased menstrual cycle regularity • decreased blood loss and decreased incidence of iron deficiency anemia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 • decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: • decreased incidence of functional ovarian cysts • decreased incidence of ectopic pregnancies Other effects: • decreased incidence of fibroadenomas and fibrocystic disease of the breast • decreased incidence of acute pelvic inflammatory disease • decreased incidence of endometrial cancer • decreased incidence of ovarian cancer DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, ORTHO-NOVUM® Tablets and MODICON® Tablets must be taken exactly as directed and at intervals not exceeding 24 hours. ORTHO-NOVUM® Tablets and MODICON® Tablets are available with the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also available. Sunday Start When taking ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON®, the first "active" tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first "active" tablet should be taken that day. Take one active tablet daily for 21 days followed by one green "reminder" tablet daily for 7 days. After 28 tablets have been taken, a new course is started the next day (Sunday). For the first cycle of a Sunday Start regimen, another method of contraception, such as a condom or spermicide, should be used until after the first 7 consecutive days of administration. If the patient misses one (1) "active" tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) "active" tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control, such as a condom or spermicide, if she has sex in the seven (7) days after missing pills. If the patient misses two (2) "active" tablets in the third week or misses three (3) or more "active" tablets in a row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling ("How to Take the Pill" section). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Day 1 Start The dosage of ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON®, for the initial cycle of therapy, is one "active" tablet administered daily from the 1st through the 21st day of the menstrual cycle, counting the first day of menstrual flow as "Day 1" followed by one green "reminder" tablet daily for 7 days. Tablets are taken without interruption for 28 days. After 28 tablets have been taken, a new course is started the next day. If the patient misses one (1) "active" tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) "active" tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control, such as a condom or spermicide, if she has sex in the seven (7) days after missing pills. If the patient misses two (2) "active" tablets in the third week or misses three (3) or more "active" tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling ("How to Take the Pill" section). The use of ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS: Nursing Mothers.) The possibility of ovulation and conception prior to initiation of medication should be considered. (See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.) ADDITIONAL INSTRUCTIONS Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 Use of oral contraceptives in the event of a missed menstrual period: 1. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued if pregnancy is confirmed. 2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. HOW SUPPLIED ORTHO-NOVUM® 7/7/7 Tablets are available in a blister card with a DIALPAK® Tablet Dispenser (unfilled) (NDC 50458-178-00). The blister card contains 28 tablets, as follows: 7 white, round, flat-faced, beveled edged tablets imprinted with "Ortho 535" on both sides (0.5 mg norethindrone and 0.035 mg ethinyl estradiol), 7 light peach, round, flat-faced, beveled edged tablets imprinted with "Ortho 75" on both sides (0.75 mg norethindrone and 0.035 mg ethinyl estradiol), 7 peach, round, flat-faced, beveled edged tablets imprinted with "Ortho 135" on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted "Ortho" on both sides containing inert ingredients. ORTHO-NOVUM® 7/7/7 Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK® Tablet Dispensers (NDC 50458-178-15). ORTHO-NOVUM® 7/7/7 is available for clinic usage in a VERIDATE® Tablet Dispenser (unfilled) and VERIDATE® refills (NDC 50458-178-20). ORTHO-NOVUM® 1/35 Tablets are available in a blister card with a DIALPAK® Tablet Dispenser (unfilled) (NDC 50458-176-00). The blister card contains 28 tablets, as follows: 21 peach, round, flat-faced, beveled edged tablets imprinted "Ortho 135" on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted "Ortho" on both sides containing inert ingredients. ORTHO-NOVUM® 1/35 Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK® Tablet Dispensers (NDC 50458-176-15). MODICON® Tablets are available in a blister card with a DIALPAK® Tablet Dispenser (unfilled) (NDC 50458-171-00). The blister card contains 28 tablets, as follows: 21 white, round, flat-faced, beveled edged tablets imprinted "Ortho 535" on both sides (0.5 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted "Ortho" on both sides containing inert ingredients. MODICON® Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK® Tablet Dispensers (NDC 50458-171-15). Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F). Keep out of reach of children. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 REFERENCES 1. 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. 2. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt. 1). N Engl J Med 1981; 305:612–618. 3. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt. 2). N Engl J Med 1981; 305:672–677. 4. Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns. Br J Obstet Gynecol 1981; 88:838-845. 5. Mann JI, Inman WH. 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Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713–1727. 91. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989; 130:878-882. 92. Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. 93. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294–298. 94. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113–118. 95. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial. Epilepsia 2007;48(3):484–489. 96. Chobanian et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42;1206–1252. 97. Brown KS, Armstrong IC, Wang A, Walker JR, Noveck RJ, Swearingen D, Allison M, Kissling JC, Kisicki J, Salazar D. Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. J Clin Pharmacol 2010;50:554–565. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 BRIEF SUMMARY PATIENT PACKAGE INSERT Oral contraceptives, also known as "birth control pills" or "the pill," are taken to prevent pregnancy and when taken correctly without missing any pills, have a failure rate of approximately 1% per year. The typical failure rate is approximately 5% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be fatal or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: • smoke • have high blood pressure, diabetes, high cholesterol • have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice or malignant or benign liver tumors. Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy, non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Do not use ORTHO-NOVUM® or MODICON® if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from combination oral contraceptives, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke. Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. 2. In rare cases, 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. However, liver cancers are rare. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your healthcare professional if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, bosentan, as well as some seizure medicines and herbal preparations containing St. John’s wort (Hypericum perforatum) may decrease oral contraceptive effectiveness. Oral contraceptives may interact with lamotrigine (LAMICTAL®), a seizure medicine used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine. Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. 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. There is insufficient evidence to rule out the possibility that the pill may cause such cancers. Taking the combination pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your healthcare professional. Your healthcare professional will take a medical and family history before prescribing oral This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. Your pharmacist should have given you the detailed patient information labeling which gives you further information which you should read and discuss with your healthcare professional. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your healthcare professional. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, your pills may not work as well. Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill taking easier or about using another method of birth control. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK. The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This is followed by 1 week of green "reminder" pills (without hormones). ORTHO-NOVUM® 7/7/7: There are 7 white "active" pills, 7 light peach "active" pills, 7 peach "active" pills and 7 green "reminder" pills. ORTHO-NOVUM® 1/35: There are 21 peach "active" pills and 7 green "reminder" pills. MODICON®: There are 21 white "active" pills and 7 green "reminder" pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a back-up method in case you miss pills. AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® are available with the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. SUNDAY START: ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. MODICON®: Take the first white "active" pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). DAY 1 START: ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack during the first 24 hours of your period. ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack during the first 24 hours of your period. MODICON®: Take the first white "active" pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: Start the next pack on the day after your last green "reminder" pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS ORTHO-NOVUM® 7/7/7: If you MISS 1 white, light peach, or peach "active" pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white or light peach "active" pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 peach "active" pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white, light peach, or peach "active" pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 ORTHO-NOVUM® 1/35: If you MISS 1 peach "active" pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 peach "active" pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 peach "active" pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE peach "active" pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. MODICON®: If you MISS 1 white "active" pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 white "active" pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white "active" pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 36 Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. A REMINDER If you forget any of the 7 green "reminder" pills in Week 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your healthcare professional. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 37 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 38 DETAILED PATIENT LABELING PLEASE NOTE: This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully. The following oral contraceptive products contain a combination of an estrogen and progestogen, the two kinds of female hormones: ORTHO-NOVUM® 7/7/7 Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each light peach tablet contains 0.75 mg norethindrone and 0.035 mg ethinyl estradiol. Each peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet contains inert ingredients. ORTHO-NOVUM® 1/35 Each peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet contains inert ingredients. MODICON® Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet contains inert ingredients. INTRODUCTION Any woman who considers using oral contraceptives (the birth control pill or the pill) should understand the benefits and risks of using this form of birth control. This patient labeling will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this labeling is not a replacement for a careful discussion between you and your healthcare professional. You should discuss the information provided in this labeling with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare professional’s advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES Oral contraceptives or "birth control pills" or "the pill" are used to prevent pregnancy and are more effective than other non-surgical methods of birth control. When they are taken correctly without missing any pills, the chance of becoming pregnant is approximately 1% (1 pregnancy per 100 women per year of use). Typical failure rates are approximately 5% per year including women who do not always take the pills exactly as directed. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other methods of birth control during the first year of use are as follows: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 39 Implant: <1% Male sterilization: <1% Injection: <1% Cervical Cap with spermicides: 20 to 40% IUD: 1 to 2% Condom alone (male): 14% Diaphragm with spermicides: 20% Condom alone (female): 21% Spermicides alone: 26% Periodic abstinence: 25% Vaginal sponge: 20 to 40% Withdrawal: 19% Female sterilization: <1% No methods: 85% WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES Do not use ORTHO-NOVUM® or MODICON® if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from combination oral contraceptives, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke. Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions: • A history of heart attack or stroke • Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes • A history of blood clots in the deep veins of your legs • An inherited problem that makes your blood clot more than normal • Chest pain (angina pectoris) • Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina • Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare professional) • Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill • Liver tumor (benign or cancerous) • Known or suspected pregnancy • Valvular heart disease with complications • Severe hypertension • Diabetes with vascular involvement • Headaches with focal neurological symptoms • If you plan to have surgery with prolonged bed rest This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 40 • Hypersensitivity to any component of this product. Tell your healthcare professional if you have ever had any of these conditions. Your healthcare professional can recommend a safer method of birth control. OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES Tell your healthcare professional if you have or have had: • Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram • Diabetes • Elevated cholesterol or triglycerides • High blood pressure • Migraine or other headaches or epilepsy • Mental depression • Gallbladder, liver, heart or kidney disease • History of scanty or irregular menstrual periods Women with any of these conditions should be checked often by their healthcare professional if they choose to use oral contraceptives. Also, be sure to inform your healthcare professional if you smoke or are on any medications. RISKS OF TAKING ORAL CONTRACEPTIVES 1. Risk of developing blood clots Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you: • First start taking birth control pills • Restart the same or different birth control pills after not using them for a month or more In particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness or injury or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your healthcare professional about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding or four weeks This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 41 after a second trimester abortion. If you are breastfeeding, you should wait until you have weaned your child before using the pill. (See also the section on Breastfeeding in General Precautions.) The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills and may be greater with longer duration of oral contraceptive use. In addition, some of these increased risks may continue for a number of years after stopping oral contraceptives. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44, it is estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers. 2. Heart attacks and strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. 3. Gallbladder disease Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. Liver tumors In rare cases, 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. However, liver cancers are rare. 5. Cancer of the reproductive organs and breasts Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 42 history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. 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. There is insufficient evidence to rule out the possibility that the pill may cause such cancers. ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility-control methods* 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker† 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker† 2.2 3.4 6.6 13.5 51.1 117.2 IUD† 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/ spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth-related. † Deaths are method-related. In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7-26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on information from older, higher-dose pills. An Advisory Committee of the FDA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 43 discussed this issue in 1989 and recommended that the benefits of low-dose oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare professional immediately: • Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) • Pain in the calf (indicating a possible clot in the leg) • Crushing chest pain or heaviness in the chest (indicating a possible heart attack) • Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) • Sudden partial or complete loss of vision (indicating a possible clot in the eye) • Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare professional to show you how to examine your breasts) • Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) • Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) • Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems) SIDE EFFECTS OF ORAL CONTRACEPTIVES 1. Vaginal bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your healthcare professional. 2. Contact lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your healthcare professional. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 44 3. Fluid retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your healthcare professional. 4. Melasma A spotty darkening of the skin is possible, particularly of the face, which may persist. 5. Other side effects Other side effects may include nausea, vomiting and diarrhea, muscle cramps, change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections, pancreatitis, skin sensitivity to the sun or ultraviolet and allergic reactions. If any of these side effects bother you, call your healthcare professional. GENERAL PRECAUTIONS 1. Missed periods and use of oral contraceptives before or during early pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare professional before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, you may be pregnant. If you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare professional immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these findings have not been seen in more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your healthcare professional about risks to your unborn child of any medication taken during pregnancy. 2. While breastfeeding If you are breastfeeding, consult your healthcare professional before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, combined oral contraceptives may decrease the amount and quality of your milk. If possible, do not use combined oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 45 of time. You should consider starting combined oral contraceptives only after you have weaned your child completely. 3. Laboratory tests If you are scheduled for any laboratory tests, tell your healthcare professional you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug interactions Tell your healthcare provider about all medicines and herbal products that you take. Some medicines and herbal products may make hormonal birth control less effective, including, but not limited to: • certain seizure medicines (carbamazepine, felbamate, oxcarbazepine, phenytoin, rufinamide, and topiramate) • aprepitant • barbiturates • bosentan • colesevelam • griseofulvin • certain combinations of HIV medicines (nelfinavir, ritonavir, ritonavir-boosted protease inhibitors) • certain non nucleoside reverse transcriptase inhibitors (nevirapine) • rifampin and rifabutin • St. John’s wort Use another birth control method (such as a condom and spermicide or diaphragm and spermicide) when you take medicines that may make ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, or MODICON® less effective. Some medicines and grapefruit juice may increase your level of the hormone ethinyl estradiol if used together, including: • acetaminophen • ascorbic acid • medicines that affect how your liver breaks down other medicines (itraconazole, ketoconazole, voriconazole, and fluconazole) • certain HIV medicines (atazanavir, indinavir) • atorvastatin This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 46 • rosuvastatin • etravirine Hormonal birth control methods may interact with lamotrigine, a seizure medicine used for epilepsy. This may increase the risk of seizures, so your healthcare provider may need to adjust the dose of lamotrigine. Women on thyroid replacement therapy may need increased doses of thyroid hormone. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. 5. Sexually transmitted diseases This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your healthcare professional. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 47 5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, your pills may not work as well. Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK. The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This is followed by 1 week of green "reminder" pills (without hormones). ORTHO-NOVUM® 7/7/7: There are 7 white "active" pills, 7 light peach "active" pills, 7 peach "active" pills and 7 green "reminder" pills. ORTHO-NOVUM® 1/35: There are 21 peach "active" pills and 7 green "reminder" pills. MODICON®: There are 21 white "active" pills and 7 green "reminder" pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a back-up method in case you miss pills. AN EXTRA, FULL PILL PACK. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 48 WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® are available with the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. SUNDAY START: ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. MODICON®: Take the first white "active" pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). DAY 1 START: ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack during the first 24 hours of your period. ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack during the first 24 hours of your period. MODICON®: Take the first white "active" pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 49 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: Start the next pack on the day after your last green "reminder" pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS ORTHO-NOVUM® 7/7/7: If you MISS 1 white, light peach, or peach "active" pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white or light peach "active" pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 peach "active" pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 50 If you MISS 3 OR MORE white, light peach, or peach "active" pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. ORTHO-NOVUM® 1/35: If you MISS 1 peach "active" pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 peach "active" pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 peach "active" pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 51 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE peach "active" pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. MODICON®: If you MISS 1 white "active" pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 52 If you MISS 2 white "active" pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white "active" pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. A REMINDER If you forget any of the 7 green "reminder" pills in Week 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 53 FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your healthcare professional. PREGNANCY DUE TO PILL FAILURE Combined Oral Contraceptives The incidence of pill failure resulting in pregnancy is approximately one percent (i.e., one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are 5%. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare professional or pharmacist. OTHER INFORMATION Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare professional if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare professional, because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 54 HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of combined oral contraceptives may provide certain benefits. They are: • menstrual cycles may become more regular • blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur. • pain or other symptoms during menstruation may be encountered less frequently • ectopic (tubal) pregnancy may occur less frequently • noncancerous cysts or lumps in the breast may occur less frequently • acute pelvic inflammatory disease may occur less frequently • oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your healthcare professional or pharmacist. They have a more technical leaflet called the Professional Labeling, which you may wish to read. Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F). Mfd. by: Janssen Ortho, LLC Manati, Puerto Rico 00674 Mfd. for: Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560 © Janssen Pharmaceuticals, Inc. 1998 Revised November 2015 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:11.105803	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017735s117,017919s099,018985s063lbl.pdf', 'application_number': 18985, 'submission_type': 'SUPPL ', 'submission_number': 63}
11,405	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	2025-02-12T13:45:11.141576	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18989scp056_advil_lbl.pdf', 'application_number': 18989, 'submission_type': 'SUPPL ', 'submission_number': 56}
11,404	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	2025-02-12T13:45:11.153089	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18989scp056_advil_lbl.pdf', 'application_number': 18989, 'submission_type': 'SUPPL ', 'submission_number': 55}
11,403	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	2025-02-12T13:45:11.275670	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18989s53lbl.pdf', 'application_number': 18989, 'submission_type': 'SUPPL ', 'submission_number': 53}
11,408	---------- USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, VASOTEC should be discontinued as soon as possible. (See WARNINGS, Fetal/Neonatal Morbidity and Mortality). VASOTEC - enalapril maleate tablet BTA Pharmaceuticals, Inc. TABLETS ® VASOTEC (ENALAPRIL MALEATE) Rx Only DESCRIPTION VASOTEC® (Enalapril Maleate) is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin converting enzyme inhibitor, enalaprilat. Enalapril maleate is chemically described as (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its empirical formula is C H N O •C H O , and its structural formula is: 20 28 2 5 4 4 4 chemical structure of enalapril maleate Enalapril maleate is a white to off-white, crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol. Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor. Enalapril maleate is supplied as 2.5 mg, 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition to the active ingredient enalapril maleate, each tablet contains the following inactive ingredients: lactose, magnesium stearate, sodium bicarbonate, and starch. The 10 mg and 20 mg tablets also contain iron oxides. CLINICAL PHARMACOLOGY Mechanism of Action This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of enalapril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with VASOTEC alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with VASOTEC plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of VASOTEC remains to be elucidated. While the mechanism through which VASOTEC lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, VASOTEC is antihypertensive even in patients with low-renin hypertension. Although VASOTEC was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril monotherapy than non- black patients. Pharmacokinetics and Metabolism Following oral administration of VASOTEC, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of VASOTEC is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency (see DOSAGE AND ADMINISTRATION). Enalaprilat is dialyzable at the rate of 62 mL/min. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C-enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters. Pharmacodynamics and Clinical Effects Hypertension Administration of VASOTEC to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients (see WARNINGS). In most patients studied, after oral administration of a single dose of enalapril, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours. At recommended doses, antihypertensive effects have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval (see DOSAGE AND ADMINISTRATION). In some patients achievement of optimal blood pressure reduction may require several weeks of therapy. The antihypertensive effects of VASOTEC have continued during long term therapy. Abrupt withdrawal of VASOTEC has not been associated with a rapid increase in blood pressure. In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of VASOTEC, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension. When given together with thiazide-type diuretics, the blood pressure lowering effects of VASOTEC are approximately additive. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving VASOTEC. In this study there was no evidence of a blunting of the antihypertensive action of VASOTEC (see PRECAUTIONS, Drug Interactions). Heart Failure In trials in patients treated with digitalis and diuretics, treatment with enalapril resulted in decreased systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure and heart size, and increased cardiac output and exercise tolerance. Heart rate was unchanged or slightly reduced, and mean ejection fraction was unchanged or increased. There was a beneficial effect on severity of heart failure as measured by the New York Heart Association (NYHA) classification and on symptoms of dyspnea and fatigue. Hemodynamic effects were observed after the first dose, and appeared to be maintained in uncontrolled studies lasting as long as four months. Effects on exercise tolerance, heart size, and severity and symptoms of heart failure were observed in placebo-controlled studies lasting from eight weeks to over one year. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Heart Failure, Mortality Trials In a multicenter, placebo-controlled clinical trial, 2,569 patients with all degrees of symptomatic heart failure and ejection fraction ≤35 percent were randomized to placebo or enalapril and followed for up to 55 months (SOLVD-Treatment). Use of enalapril was associated with an 11 percent reduction in all-cause mortality and a 30 percent reduction in hospitalization for heart failure. Diseases that excluded patients from enrollment in the study included severe stable angina (>2 attacks/day), hemodynamically significant valvular or outflow tract obstruction, renal failure (creatinine >2.5 mg/dL), cerebral vascular disease (e.g., significant carotid artery disease), advanced pulmonary disease, malignancies, active myocarditis and constrictive pericarditis. The mortality benefit associated with enalapril does not appear to depend upon digitalis being present. A second multicenter trial used the SOLVD protocol for study of asymptomatic or minimally symptomatic patients. SOLVD-Prevention patients, who had left ventricular ejection fraction ≤35% and no history of symptomatic heart failure, were randomized to placebo (n=2117) or enalapril (n=2111) and followed for up to 5 years. The majority of patients in the SOLVD- Prevention trial had a history of ischemic heart disease. A history of myocardial infarction was present in 80 percent of patients, current angina pectoris in 34 percent, and a history of hypertension in 37 percent. No statistically significant mortality effect was demonstrated in this population. Enalapril-treated subjects had 32% fewer first hospitalizations for heart failure, and 32% fewer total heart failure hospitalizations. Compared to placebo, 32 percent fewer patients receiving enalapril developed symptoms of overt heart failure. Hospitalizations for cardiovascular reasons were also reduced. There was an insignificant reduction in hospitalizations for any cause in the enalapril treatment group (for enalapril vs. placebo, respectively, 1166 vs. 1201 first hospitalizations, 2649 vs. 2840 total hospitalizations), although the study was not powered to look for such an effect. The SOLVD-Prevention trial was not designed to determine whether treatment of asymptomatic patients with low ejection fraction would be superior, with respect to preventing hospitalization, to closer follow-up and use of enalapril at the earliest sign of heart failure. However, under the conditions of follow-up in the SOLVD-Prevention trial (every 4 months at the study clinic; personal physician as needed), 68% of patients on placebo who were hospitalized for heart failure had no prior symptoms recorded which would have signaled initiation of treatment. The SOLVD-Prevention trial was also not designed to show whether enalapril modified the progression of underlying heart disease. In another multicenter, placebo-controlled trial (CONSENSUS) limited to patients with NYHA Class IV congestive heart failure and radiographic evidence of cardiomegaly, use of enalapril was associated with improved survival. The results are shown in the following table. SURVIVAL (%) Six Months One Year VASOTEC (n=127) 74 64 Placebo (n=126) 56 48 In both CONSENSUS and SOLVD-Treatment trials, patients were also usually receiving This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda digitalis, diuretics or both. Clinical Pharmacology in Pediatric Patients A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female pediatric patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg enalapril maleate. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours and the mean urinary recovery of total enalapril and enalaprilat in 24 hours was 68% of the administered dose. Conversion of enalapril to enalaprilat was in the range of 63-76%. The overall results of this study indicate that the pharmacokinetics of enalapril in hypertensive children aged 2 months to ≤16 years are consistent across the studied age groups and consistent with pharmacokinetic historic data in healthy adults. In a clinical study involving 110 hypertensive pediatric patients 6 to 16 years of age, patients who weighed <50 kg received either 0.625, 2.5 or 20 mg of enalapril daily and patients who weighed ≥50 kg received either 1.25, 5, or 40 mg of enalapril daily. Enalapril administration once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of enalapril was consistent across all subgroups (age, Tanner stage, gender, race). However, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. In this study, VASOTEC was generally well tolerated. In the above pediatric studies, enalapril maleate was given as tablets of VASOTEC and for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form, enalapril was administered in a suspension formulation (see Preparation of Suspension under DOSAGE AND ADMINISTRATION). INDICATIONS AND USAGE Hypertension VASOTEC is indicated for the treatment of hypertension. VASOTEC is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of VASOTEC and thiazides are approximately additive. Heart Failure VASOTEC is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. In these patients VASOTEC improves symptoms, increases survival, and decreases the frequency of hospitalization (see CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials). Asymptomatic Left Ventricular Dysfunction In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤35 percent), VASOTEC decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure (see CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials). In using VASOTEC consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda that VASOTEC does not have a similar risk (see WARNINGS). In considering use of VASOTEC, it should be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS, Head and Neck Angioedema). CONTRAINDICATIONS VASOTEC is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. WARNINGS Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including VASOTEC) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including VASOTEC. This may occur at any time during treatment. In such cases VASOTEC should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS). Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS). Anaphylactoid reactions during desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension Excessive hypotension is rare in uncomplicated hypertensive patients treated with VASOTEC alone. Patients with heart failure given VASOTEC commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy (see DOSAGE AND ADMINISTRATION). Patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with VASOTEC in patients at risk for excessive hypotension who are able to tolerate such adjustments (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS). In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of VASOTEC, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of VASOTEC or concomitant diuretic may be necessary. Neutropenia/Agranulocytosis Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Fetal/Neonatal Morbidity and Mortality ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. In a published restrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been repeated. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of VASOTEC as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, VASOTEC should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure. No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including VASOTEC, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when VASOTEC has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or VASOTEC may be required. Evaluation of patients with hypertension or heart failure should always include assessment of renal function (see DOSAGE AND ADMINISTRATION). Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. In clinical trials in heart failure, hyperkalemia was observed in 3.8 percent of patients but was not a cause for discontinuation. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with VASOTEC (see Drug Interactions). Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Information for Patients Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin converting enzyme inhibitors, including enalapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician. Hypotension: Patients should be cautioned to report lightheadedness, especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician. Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACE inhibitors. These patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with enalapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Drug Interactions Hypotension — Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION). Agents Causing Renin Release: The antihypertensive effect of VASOTEC is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-steroidal Anti-inflammatory Agents: In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of enalapril may result in a further deterioration of renal function. These effects are usually reversible. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving VASOTEC. In this study there was no evidence of a blunting of the antihypertensive action of VASOTEC. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Other Cardiovascular Agents: VASOTEC has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interactions. Agents Increasing Serum Potassium: VASOTEC attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure receiving VASOTEC. Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant VASOTEC and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including VASOTEC. 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 There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis. Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis). Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters) (see WARNINGS, Fetal/Neonatal Morbidity and Mortality). Nursing Mothers Enalapril and enalaprilat have been detected in human breast milk. Because of the potential for serious adverse reactions in nursing infants from enalapril, a decision should be made whether to discontinue nursing or to discontinue VASOTEC, taking into account the importance of the drug to the mother. Pediatric Use Antihypertensive effects of VASOTEC have been established in hypertensive pediatric patients age 1 month to 16 years. Use of VASOTEC in these age groups is supported by evidence from adequate and well-controlled studies of VASOTEC in pediatric and adult patients as well as by published literature in pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients and DOSAGE AND ADMINISTRATION). VASOTEC is not recommended in neonates and in pediatric patients with glomerular filtration 2 rate <30 mL/min/1.73 m , as no data are available. ADVERSE REACTIONS VASOTEC has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. VASOTEC has been found to be generally well tolerated in controlled clinical trials involving 2987 patients. For the most part, adverse experiences were mild and transient in nature. In clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 3.3 percent of patients with hypertension and in 5.7 percent of patients with heart failure. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension the overall percentage of patients treated with VASOTEC reporting adverse experiences was comparable to placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fatigue 3.0 (<0.1) 1.2 (<0.1) 2.6 0.0 Orthostatic Effects 1.1 (0.1) 0.9 1.4 (0.4) 0.4 1.3 (0.1) 0.9 1.4 (<0.1) 1.4 (0.2) 1.7 1.7 5.2 (0.3) 4.3 (0.4) 9.1 4.3 HEART FAILURE Asthenia Digestive Diarrhea Nausea Nervous/Psychiatric Headache Dizziness Respiratory Cough Skin Rash ole VASOTEC (n = 2314) Incidence (discontinuation) Placebo (n = 230) Incidence Body As A Wh HYPERTENSION Adverse experiences occurring in greater than one percent of patients with hypertension treated with VASOTEC in controlled clinical trials are shown below. In patients treated with VASOTEC, the maximum duration of therapy was three years; in placebo treated patients the maximum duration of therapy was 12 weeks. Adverse experiences occurring in greater than one percent of patients with heart failure treated with VASOTEC are shown below. The incidences represent the experiences from both controlled and uncontrolled clinical trials (maximum duration of therapy was approximately one year). In the placebo treated patients, the incidences reported are from the controlled trials (maximum duration of therapy is 12 weeks). The percentage of patients with severe heart failure (NYHA Class IV) was 29 percent and 43 percent for patients treated with VASOTEC and placebo, respectively. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Incidence (discontinuation) Body As A Whole Incidence Orthostatic Effects 2.2 (0.1) 0.3 Syncope 2.2 (0.1) 0.9 Chest Pain 2.1 (0.0) 2.1 Fatigue 1.8 (0.0) 1.8 Abdominal Pain 1.6 (0.4) 2.1 Asthenia 1.6 (0.1) 0.3 Cardiovascular Hypotension 6.7 (1.9) 0.6 Orthostatic Hypotension 1.6 (0.1) 0.3 Angina Pectoris 1.5 (0.1) 1.8 Myocardial Infarction 1.2 (0.3) 1.8 Digestive Diarrhea 2.1 (0.1) 1.2 Nausea 1.3 (0.1) 0.6 Vomiting 1.3 (0.0) 0.9 Nervous/Psychiatric Dizziness 7.9 (0.6) 0.6 VASOTEC (n = 673) Placebo (n = 339) Headache 1.8 (0.1) 0.9 Vertigo 1.6 (0.1) 1.2 Respiratory Cough 2.2 (0.0) 0.6 Bronchitis 1.3 (0.0) 0.9 Dyspnea 1.3 (0.1) 0.4 Pneumonia 1.0 (0.0) 2.4 Skin This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rash 1.3 (0.0) 2.4 Urogenital Urinary Tract Infection 1.3 (0.0) 2.4 Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity. Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions). Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; palpitation, Raynaud's phenomenon. Digestive: Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, dyspepsia, constipation, glossitis, stomatitis, dry mouth. Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression. Musculoskeletal: Muscle cramps. Nervous/Psychiatric: Depression, confusion, ataxia, somnolence, insomnia, nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality. Respiratory: Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis. Skin: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity. Special Senses: Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing. Urogenital: Renal failure, oliguria, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), flank pain, gynecomastia, impotence. Miscellaneous: A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Angioedema: Angioedema has been reported in patients receiving VASOTEC, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with VASOTEC should be discontinued and appropriate therapy instituted immediately (see WARNINGS). Hypotension: In the hypertensive patients, hypotension occurred in 0.9 percent and syncope This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda occurred in 0.5 percent of patients following the initial dose or during extended therapy. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. In heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure (see WARNINGS). Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality. Cough: See PRECAUTIONS, Cough. Pediatric Patients The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients. Clinical Laboratory Test Findings Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia. Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with VASOTEC alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see PRECAUTIONS). In patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of VASOTEC and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients. Hematology: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with VASOTEC but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Liver Function Tests Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure). OVERDOSAGE Limited data are available in regard to overdosage in humans. Single oral doses of enalapril above 1,000 mg/kg and ≥1,775 mg/kg were associated with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal Status Creatinine- Clearance mL/min Initial Dose mg/day Normal Renal Function >80 mL/min 5 mg Mild Impairment ≤80 >30 mL/min 5 mg lethality in mice and rats, respectively. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis (see WARNINGS, Anaphylactoid reactions during membrane exposure). DOSAGE AND ADMINISTRATION Hypertension In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of VASOTEC. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with VASOTEC to reduce the likelihood of hypotension (see WARNINGS). If the patient's blood pressure is not controlled with VASOTEC alone, diuretic therapy may be resumed. If the diuretic cannot be discontinued an initial dose of 2.5 mg should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). The recommended initial dose in patients not on diuretics is 5 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 10 to 40 mg per day administered in a single dose or two divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice daily administration should be considered. If blood pressure is not controlled with VASOTEC alone, a diuretic may be added. Concomitant administration of VASOTEC with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS). Dosage Adjustment in Hypertensive Patients with Renal Impairment The usual dose of enalapril is recommended for patients with a creatinine clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance ≤30 mL/min (serum creatinine ≥3 mg/dL), the first dose is 2.5 mg once daily. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dialysis Patients — 2.5 mg on dialysis days * † Moderate to Severe ≤30 mL/min 2.5 mg Impairment * See WARNINGS, Anaphylactoid reactions during membrane exposure † Dosage on nondialysis days should be adjusted depending on the blood pressure response. Heart Failure VASOTEC is indicated for the treatment of symptomatic heart failure, usually in combination with diuretics and digitalis. In the placebo-controlled studies that demonstrated improved survival, patients were titrated as tolerated up to 40 mg, administered in two divided doses. The recommended initial dose is 2.5 mg. The recommended dosing range is 2.5 to 20 mg given twice a day. Doses should be titrated upward, as tolerated, over a period of a few days or weeks. The maximum daily dose administered in clinical trials was 40 mg in divided doses. After the initial dose of VASOTEC, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of VASOTEC does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. Asymptomatic Left Ventricular Dysfunction In the trial that demonstrated efficacy, patients were started on 2.5 mg twice daily and were titrated as tolerated to the targeted daily dose of 20 mg (in divided doses). After the initial dose of VASOTEC, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of VASOTEC does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia In patients with heart failure who have hyponatremia (serum sodium less than 130 mEq/L) or with serum creatinine greater than 1.6 mg/dL, therapy should be initiated at 2.5 mg daily under close medical supervision (see DOSAGE AND ADMINISTRATION, Heart Failure, WARNINGS and PRECAUTIONS, Drug Interactions). The dose may be increased to 2.5 mg b.i.d., then 5 mg b.i.d. and higher as needed, usually at intervals of four days or more if at the time of dosage adjustment there is not excessive hypotension or significant deterioration of renal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda function. The maximum daily dose is 40 mg. Pediatric Hypertensive Patients The usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. Dosage should be adjusted according to blood pressure response. Doses above 0.58 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients). VASOTEC is not recommended in neonates and in pediatric patients with glomerular filtration 2 rate <30 mL/min/1.73 m , as no data are available. Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension) Add 50 mL of Bicitra®1 to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of VASOTEC and shake for at least 2 minutes. Let concentrate stand for 60 minutes. Following the 60-minute hold time, shake the concentrate for an additional minute. Add 150 mL of Ora-Sweet SF™ 2 to the concentrate in the PET bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days. Shake the suspension before each use. 1 Registered trademark of Alza Corporation 2 Trademark of Paddock Laboratories, Inc. HOW SUPPLIED VASOTEC Tablets, 2.5 mg, are white, oval shaped tablet with "MSD14" and scored on one side and scored on the other. They are supplied as follows: NDC 64455-140-30 bottles of 30 (with desiccant) NDC 64455-140-90 unit of use bottles of 90 (with desiccant) VASOTEC Tablets, 5 mg, are white, rounded triangle shaped tablet with "MSD712" on one side and scored on the other. They are supplied as follows: NDC 64455-141-30 bottles of 30 (with desiccant) NDC 64455-141-90 unit of use bottles of 90 (with desiccant) NDC 64455-141-10 bottles of 1,000 (with desiccant) VASOTEC Tablets, 10 mg, are rust red, rounded triangle shaped tablet with "MSD713" on one side and scored on the other. They are supplied as follows: NDC 64455-142-30 bottles of 30 (with desiccant) NDC 64455-142-90 unit of use bottles of 90 (with desiccant) NDC 64455-142-10 bottles of 1,000 (with desiccant) VASOTEC Tablets, 20 mg, are peach, rounded triangle shaped tablet with "MSD714" on one side and scored on the other. They are supplied as follows: NDC 64455-143-30 bottles of 30 (with desiccant) NDC 64455-143-90 unit of use bottles of 90 (with desiccant) NDC 64455-143-10 bottles of 1,000 (with desiccant) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture. Dispense in a tight container as per USP, if product package is subdivided. Vasotec® is a registered trademark of Biovail Laboratories International SRL Manufactured by: Merck Sharp & Dohme Ltd. Shotton Lane, Cramlington Northumberland, UK NE23 3JU For: BTA Pharmaceuticals, Inc. Bridgewater, NJ 08807, USA Tablets made in the United Kingdom ® BIOVAIL Rev. 03/08 LB0026-04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:11.411237	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018998s071lbl.pdf', 'application_number': 18998, 'submission_type': 'SUPPL ', 'submission_number': 71}
11,407	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/ ---------------------------------------------------- KAREN M MAHONEY 12/16/2015 Reference ID: 3862689 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:11.466588	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018989Orig1s084lbl.pdf', 'application_number': 18989, 'submission_type': 'SUPPL ', 'submission_number': 84}

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