Acamprosate

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 ).

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 mL/min to 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 mL/min to 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) ] .

WARNINGS AND PRECAUTIONS • Dose reduction is required for patients with moderate renal impairment ( 5.1 ). • Monitor patients for depression or suicidal ideation and prompt patients, families, and caregivers to report such symptoms to the health care provider ( 5.2 ). 5.1 Renal Impairment Treatment with acamprosate calcium in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min) requires a dose reduction [see Dosage and Administration ( 2.1 )] . Acamprosate calcium is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min) [see Dosage and Administration ( 2.1 ), Contraindications ( 4.2 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] . 5.2 Suicidality and Depression In controlled clinical trials of acamprosate calcium, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in acamprosate calcium-treated patients than in patients treated with placebo (1.4% vs. 0.5% in studies of 6 months or less; 2.4% vs. 0.8% in year-long studies). Completed suicides occurred in 3 of 2272 (0.13%) patients in the pooled acamprosate group from all controlled studies and 2 of 1962 patients (0.10%) in the placebo group. Adverse events coded as "depression" were reported at similar rates in acamprosate calcium-treated and placebo-treated patients. Although many of these events occurred in the context of alcohol relapse, and the interrelationship between alcohol dependence, depression and suicidality is well-recognized and complex, no consistent pattern of relationship between the clinical course of recovery from alcoholism and the emergence of suicidality was identified. Alcohol-dependent patients, including those patients being treated with acamprosate calcium, should be monitored for the development of symptoms of depression or suicidal thinking. Families and caregivers of patients being treated with acamprosate calcium should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient's health care provider. 5.3 Alcohol Withdrawal Use of acamprosate calcium does not eliminate or diminish withdrawal symptoms.

CONTRAINDICATIONS • Acamprosate calcium is contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components ( 4.1 ). • Acamprosate calcium is contraindicated in patients with severe renal impairment ( 4.2 ). 4.1 Hypersensitivity to Acamprosate Calcium Acamprosate calcium is contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components. 4.2 Severe Renal Impairment Acamprosate calcium is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min) [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] .

DRUG INTERACTIONS Acamprosate does not affect the pharmacokinetics of alcohol. The pharmacokinetics of acamprosate are not affected by alcohol, diazepam, or disulfiram, and clinically important interactions between naltrexone and acamprosate were not observed [see Clinical Pharmacology ( 12.3 )] .

ADVERSE REACTIONS Common adverse events that occurred in any acamprosate calcium 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 Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 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 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 for up to one year, including over 2000 acamprosate calcium-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-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-treated patients. Only diarrhea was associated with the discontinuation of more than 1% of patients (2% of acamprosate calcium-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-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 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 Treatment Group in Controlled Clinical Trials with Spontaneously Reported Adverse Events. Body System/ Preferred Term Number of Patients (%) with Events Acamprosate Calcium 1332 mg/day Acamprosate Calcium 1998 mg/day includes events coded as "fracture" by sponsor; Acamprosate Calcium Pooled includes events coded as "nervousness" by sponsor 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 258 patients treated with acamprosate calcium 2000 mg/day, using a different dosage strength and regimen. 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 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. 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 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 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 Following is a list of terms that reflect treatment-emergent adverse events reported by patients treated with acamprosate calcium in 20 clinical trials (4461 patients treated with acamprosate calcium, 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, hy

Mechanism of Action The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure is hypothesized to alter the normal balance between neuronal excitation and inhibition. In vitro and in vivo studies in animals have provided evidence to suggest acamprosate may interact with glutamate and GABA neurotransmitter systems centrally, and has led to the hypothesis that acamprosate restores this balance.