Acamprosate Calcium Enteric-Coated

1 INDICATIONS AND USAGE Acamprosate calcium delayed-release tablets are indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. Treatment with acamprosate calcium delayed-release tablets should be part of a comprehensive management program that includes psychosocial support. The efficacy of acamprosate calcium delayed-release tablets in promoting abstinence has not been demonstrated in subjects who have not undergone detoxification and not achieved alcohol abstinence prior to beginning acamprosate calcium delayed-release tablets treatment. The efficacy of acamprosate calcium delayed-release tablets in promoting abstinence from alcohol in polysubstance abusers has not been adequately assessed. • Acamprosate calcium delayed-release tablets are indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation ( 1 , 14 ). • Treatment with acamprosate calcium delayed-release tablets should be part of a comprehensive management program that includes psychosocial support ( 1 ).

2 DOSAGE AND ADMINISTRATION The recommended dose of acamprosate calcium delayed-release tablets is two 333 mg tablets (each dose should total 666 mg) taken three times daily. A lower dose may be effective in some patients. Although dosing may be done without regard to meals, dosing with meals was employed during clinical trials and is suggested in those patients who regularly eat three meals daily. Treatment with acamprosate calcium delayed-release tablets should be initiated as soon as possible after the period of alcohol withdrawal, when the patient has achieved abstinence, and should be maintained if the patient relapses. Acamprosate calcium delayed-release tablets should be used as part of a comprehensive psychosocial treatment program. • Recommended dose: 666 mg (two 333 mg tablets) taken three times daily ( 2 ). • Dose reduction to one 333 mg tablet taken three times daily for patients with moderate renal impairment (creatinine clearance 30-50 mL/min) ( 2.1 ). • Acamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min) ( 2.1 , 4.2 , 5.1 , 8.6 , 12.3 ). 2.1 Dosage in Renal Impairment For patients with moderate renal impairment (creatinine clearance of 30-50 mL/min), a starting dose of one 333 mg tablet taken three times daily is recommended. Acamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min) [ see Contraindications (4.2) , Warnings and Precautions (5.1) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS Common adverse events that occurred in any acamprosate calcium delayed-release tablets treatment group at a rate of 3% or greater and greater than the placebo group in controlled clinical trials with spontaneously reported adverse events are: accidental injury, asthenia, pain, anorexia, diarrhea, flatulence, nausea, anxiety, depression, dizziness, dry mouth, insomnia, paresthesia, pruritus and sweating ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Clinically significant serious adverse reactions associated with acamprosate calcium delayed-release tablets described elsewhere in labeling include suicidality and depression and acute kidney failure [see Warnings and Precautions (5.2) , and Adverse Reactions (6.2) ] . The adverse event data described below reflect the safety experience in over 7000 patients exposed to acamprosate calcium delayed-release tablets for up to one year, including over 2000 acamprosate calcium delayed-release tablets-exposed patients who participated in placebo-controlled trials. Adverse Events Leading to Discontinuation In placebo-controlled trials of 6 months or less, 8% of acamprosate calcium delayed-release tablets-treated patients discontinued treatment due to an adverse event, as compared to 6% of patients treated with placebo. In studies longer than 6 months, the discontinuation rate due to adverse events was 7% in both the placebo-treated and the acamprosate calcium delayed-release tablets-treated patients. Only diarrhea was associated with the discontinuation of more than 1% of patients (2% of acamprosate calcium delayed-release tablets-treated vs. 0.7% of placebo-treated patients). Other events, including nausea, depression, and anxiety, while accounting for discontinuation in less than 1% of patients, were nevertheless more commonly cited in association with discontinuation in acamprosate calcium delayed-release tablets-treated patients than in placebo-treated patients. Common Adverse Events Reported in Controlled Trials Common adverse events were collected spontaneously in some controlled studies and using a checklist in other studies. The overall profile of adverse events was similar using either method. Table 1 shows those events that occurred in any acamprosate calcium delayed-release tablets treatment group at a rate of 3% or greater and greater than the placebo group in controlled clinical trials with spontaneously reported adverse events. The reported frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed, without regard to the causal relationship of the events to the drug. Table 1. Events Occurring at a Rate of at Least 3% and Greater than Placebo in any Acamprosate Calcium Delayed-Release Tablets Treatment Group in Controlled Clinical Trials with Spontaneously Reported Adverse Events. Body System/ Preferred Term Number of Patients (%) with Events Acamprosate Calcium Delayed-Release Tablets 1332 mg/day Acamprosate Calcium Delayed-Release Tablets 1998 mg/day includes 258 patients treated with acamprosate calcium 2000 mg/day, using a different dosage strength and regimen. Acamprosate Calcium Delayed-Release Tablets Pooled includes all patients in the first two columns as well as 83 patients treated with acamprosate calcium 3000 mg/day, using a different dosage strength and regimen. Placebo Number of patients in Treatment Group 397 1539 2019 1706 Number (%) of patients with an AE 248 (62%) 910 (59%) 1231 (61%) 955 (56%) Body as a Whole 121 (30%) 513 (33%) 685 (34%) 517 (30%) Accidental Injury includes events coded as “fracture” by sponsor; 17 (4%) 44 (3%) 70 (3%) 52 (3%) Asthenia 29 (7%) 79 (5%) 114 (6%) 93 (5%) Pain 6 (2%) 56 (4%) 65 (3%) 55 (3%) Digestive System 85 (21%) 440 (29%) 574 (28%) 344 (20%) Anorexia 20 (5%) 35 (2%) 57 (3%) 44 (3%) Diarrhea 39 (10%) 257 (17%) 329 (16%) 166 (10%) Flatulence 4 (1%) 55 (4%) 63 (3%) 28 (2%) Nausea 11 (3%) 69 (4%) 87 (4%) 58 (3%) Nervous System 150 (38%) 417 (27%) 598 (30%) 500 (29%) Anxiety includes events coded as “nervousness” by sponsor 32 (8%) 80 (5%) 118 (6%) 98 (6%) Depression 33 (8%) 63 (4%) 102 (5%) 87 (5%) Dizziness 15 (4%) 49 (3%) 67 (3%) 44 (3%) Dry mouth 13 (3%) 23 (1%) 36 (2%) 28 (2%) Insomnia 34 (9%) 94 (6%) 137 (7%) 121 (7%) Paresthesia 11 (3%) 29 (2%) 40 (2%) 34 (2%) Skin and Appendages 26 (7%) 150 (10%) 187 ( 9%) 169 (10%) Pruritus 12 (3%) 68 (4%) 82 (4%) 58 (3%) Sweating 11 (3%) 27 (2%) 40 (2%) 39 (2%) Concomitant Therapies In clinical trials, the safety profile in subjects treated with acamprosate calcium delayed-release tablets concomitantly with anxiolytics, hypnotics and sedatives (including benzodiazepines), or non-opioid analgesics was similar to that of subjects taking placebo with these concomitant medications. Patients taking acamprosate calcium delayed-release tablets concomitantly with antidepressants more commonly reported both weight gain and weight loss, compared with patients taking either medication alone. Other Events Observed During the Premarketing Evaluation of Acamprosate Calcium Delayed-Release Tablets Following is a list of terms that reflect treatment-emergent adverse events reported by patients treated with acamprosate calcium delayed-release tablets in 20 clinical trials (4461 patients treated with acamprosate calcium delayed-release tablets, 3526 of whom received the maximum recommended dose of 1998 mg/day for up to one year in duration). This listing does not include those events already listed above; events for which a drug cause was considered remote; event terms which were so general as to be uninformative; and events reported only once which were not likely to be acutely life-threatening. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the summary of adverse events in controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a Whole: Frequent: headache, abdominal pain, back pain, infection, flu syndrome, chest pain, chills, suicide attempt; Infrequent: fever, intentional overdose, malaise, allergic reaction, abscess, neck pain, hernia, intentional injury; Rare: ascites, face edema, photosensitivity reaction, abdomen enlarged, sudden death. Cardiovascular System: Frequent: palpitation, syncope; Infrequent: hypotension, tachycardia, hemorrhage, angina pectoris, migraine, varicose vein, myocardial infarct, phlebitis, postural hypotension; Rare: heart failure, mesenteric arterial occlusion, cardiomyopathy, deep thrombophlebitis, shock. Digestive System: Frequent: vomiting, dyspepsia, constipation, increased appetite; Infrequent: liver function tests abnormal, gastroenteritis, gastritis, dysphagia, eructation, gastrointestinal hemorrhage, pancreatitis, rectal hemorrhage, liver cirrhosis, esophagitis, hematemesis, nausea and vomiting, hepatitis; Rare: melena, stomach ulcer, cholecystitis, colitis, duodenal ulcer, mouth ulceration, carcinoma of liver. Endocrine System: Rare: goiter, hypothyroidism. Hemic and Lymphatic System: Infrequent: anemia, ecchymosis, eosinophilia, lymphocytosis, thrombocytopenia; Rare: leukopenia, lymphadenopathy, monocytosis. Metabolic and Nutritional Disorders: Frequent: peripheral edema, weight gain; Infrequent: weight loss, hyperglycemia, SGOT increased, SGPT increased, gout, thirst, hyperuricemia, diabetes mellitus, avitaminosis, bilirubinemia; Rare: alkaline phosphatase increased, creatinine increased, hyponatremia, lactic dehydrogenase increased. Musculoskeletal System: Frequent: myalgia, arthralgia; Infrequent: leg cramps; Rare: rheumatoid arthritis, myopathy. Nervous System: Frequent: somnolence, libido decreased, amnesia, thinking abnormal, tremor, vasodilatation, hypertension; Infrequent: convulsion, confusion, libido increased, vertigo, withdrawal syndrome, apathy, suicidal ideation, neuralgia, hostility, agitation, neurosis, abnormal dreams, hallucinations, hypesthesia; Rare: alcohol craving, psychosis, hyperkinesia, twitching, depersonalization, increased salivation, paranoid reaction, torticollis, encephalopathy, manic reaction. Respiratory System: Frequent: rhinitis, cough increased, dyspnea, pharyngitis, bronchitis; Infrequent: asthma, epistaxis, pneumonia; Rare: laryngismus, pulmonary embolus. Skin and Appendages: Frequent: rash; Infrequent: acne, eczema, alopecia, maculopapular rash, dry skin, urticaria, exfoliative dermatitis, vesiculobullous rash; Rare: psoriasis. Special Senses: Frequent: abnormal vision, taste perversion; Infrequent: tinnitus, amblyopia, deafness; Rare: ophthalmitis, diplopia, photophobia. Urogenital System: Frequent: impotence; Infrequent: metrorrhagia, urinary frequency, urinary tract infection, sexual function abnormal, urinary incontinence, vaginitis; Rare: kidney calculus, abnormal ejaculation, hematuria, menorrhagia, nocturia, polyuria, urinary urgency. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of acamprosate calcium delayed-release tablets. 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. Serious Adverse Events Observed During the Non-U.S. Postmarketing Evaluation of Acamprosate Calcium Delayed-Release Tablets The serious adverse event of acute kidney failure has been reported to be temporally associated with acamprosate calcium delayed-release tablets treatment in at least 3 patients and is not described elsewhere in the labeling.

12.3 Pharmacokinetics Absorption The absolute bioavailability of acamprosate calcium delayed-release tablets after oral administration is about 11%. Steady-state plasma concentrations of acamprosate are reached within 5 days of dosing. Steady-state peak plasma concentrations after acamprosate calcium delayed-release tablets doses of 2 x 333 mg tablets three times daily average 350 ng/mL and occur at 3-8 hours post-dose. Coadministration of acamprosate calcium delayed-release tablets with food decreases bioavailability as measured by C max and AUC, by approximately 42% and 23%, respectively. The food effect on absorption is not clinically significant and no adjustment of dose is necessary. Distribution The volume of distribution for acamprosate following intravenous administration is estimated to be 72-109 liters (approximately 1 L/kg) . Plasma protein binding of acamprosate is negligible. Metabolism Acamprosate does not undergo metabolism. Elimination After oral dosing of 2 x 333 mg of acamprosate calcium delayed-release tablets, the terminal half-life ranges from approximately 20-33 hours. Following oral administration of acamprosate calcium delayed-release tablets, the major route of excretion is via the kidneys as acamprosate. Special Populations Gender Acamprosate calcium delayed-release tablets do not exhibit any significant pharmacokinetic differences between male and female subjects. Age The pharmacokinetics of acamprosate calcium delayed-release tablets have not been evaluated in a geriatric population. However, since renal function diminishes in elderly patients and acamprosate is excreted unchanged in urine, acamprosate plasma concentrations are likely to be higher in the elderly population compared to younger adults. Pediatrics The pharmacokinetics of acamprosate calcium delayed-release tablets have not been evaluated in a pediatric population. Renal Impairment Peak plasma concentrations after administration of a single dose of 2 x 333 mg acamprosate calcium delayed-release tablets to patients with moderate or severe renal impairment were about 2-fold and 4-fold higher, respectively, compared to healthy subjects. Similarly, elimination half-life was about 1.8-fold and 2.6-fold longer, respectively, compared to healthy subjects. There is a linear relationship between creatinine clearance values and total apparent plasma clearance, renal clearance and plasma half-life of acamprosate. A dose of 1 x 333 mg acamprosate calcium delayed-release tablets, three times daily, is recommended in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min, [ see Use in Specific Populations (8.6) ] . Acamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min) [ see Dosage and Administration (2.1) , Contraindications (4.2) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.6) ] . Hepatic Impairment Acamprosate is not metabolized by the liver and the pharmacokinetics of acamprosate calcium delayed-release tablets are not altered in patients with mild to moderate hepatic impairment (groups A and B of the Child-Pugh classification). No adjustment of dosage is recommended in such patients. Alcohol-Dependent Subjects A cross-study comparison of acamprosate calcium delayed-release tablets at doses of 2 x 333 mg three times daily indicated similar pharmacokinetics between alcohol-dependent subjects and healthy subjects. Drug-Drug Interactions Acamprosate had no inducing potential on the cytochrome CYP1A2 and 3A4 systems, and in vitro inhibition studies suggest that acamprosate does not inhibit in vivo metabolism mediated by cytochrome CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. The pharmacokinetics of acamprosate calcium delayed-release tablets were unaffected when co-administered with alcohol, disulfiram or diazepam. Similarly, the pharmacokinetics of ethanol, diazepam and nordiazepam, imipramine and desipramine, naltrexone and 6-beta naltrexol were unaffected following co-administration with acamprosate calcium delayed-release tablets. However, co-administration of acamprosate calcium delayed-release tablets with naltrexone led to a 33% increase in the C max and a 25% increase in the AUC of acamprosate. No adjustment of dosage is recommended in such patients.