Acamprosate Calcium

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) ] .

4 CONTRAINDICATIONS Acamprosate calcium delayed-release tablets are contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components ( 4.1 ). Acamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment ( 4.2 ). 4.1 Hypersensitivity to Acamprosate Calcium Acamprosate calcium delayed-release tablets are contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components. 4.2 Severe Renal Impairment 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) , Warnings and Precautions (5.1) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ].

5 WARNINGS AND PRECAUTIONS Contains sodium sulfite, 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. 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 delayed-release tablets in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) requires a dose reduction [see Dosage and Administration (2.1) ] . 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) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . 5.2 Suicidality and Depression In controlled clinical trials of acamprosate calcium delayed-release tablets, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in acamprosate calcium delayed-release tablets-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 delayed-release tablets-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 delayed-release tablets, should be monitored for the development of symptoms of depression or suicidal thinking. Families and caregivers of patients being treated with acamprosate calcium delayed-release tablets 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 delayed-release tablets does not eliminate or diminish withdrawal symptoms.

7 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) ] .

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.

8.1 Pregnancy Pregnancy Category C Teratogenic Effects Acamprosate calcium has been shown to be teratogenic in rats when given in doses that are approximately equal to the human dose (on a mg/m 2 basis) and in rabbits when given in doses that are approximately 3 times the human dose (on a mg/m 2 basis). Acamprosate calcium produced a dose-related increase in the number of fetuses with malformations in rats at oral doses of 300 mg/kg/day or greater (approximately equal to the maximum recommended human daily (MRHD) oral dose on a mg/m 2 basis). The malformations included hydronephrosis, malformed iris, retinal dysplasia, and retroesophageal subclavian artery. No findings were observed at an oral dose of 50 mg/kg/day (approximately one-fifth the MRHD oral dose on a mg/m 2 basis). An increased incidence of hydronephrosis was also noted in Burgundy Tawny rabbits at oral doses of 400 mg/kg/day or greater (approximately 3 times the MRHD oral dose on a mg/m 2 basis). No developmental effects were observed in New Zealand white rabbits at oral doses up to 1000 mg/kg/day (approximately 8 times the MRHD oral dose on a mg/m 2 basis). The findings in animals should be considered in relation to known adverse developmental effects of ethyl alcohol, which include the characteristics of fetal alcohol syndrome (craniofacial dysmorphism, intrauterine and postnatal growth retardation, retarded psychomotor and intellectual development) and milder forms of neurological and behavioral disorders in humans. There are no adequate and well controlled studies in pregnant women. Acamprosate calcium delayed-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects A study conducted in pregnant mice that were administered acamprosate calcium by the oral route starting on Day 15 of gestation through the end of lactation on postnatal day 28 demonstrated an increased incidence of still-born fetuses at doses of 960 mg/kg/day or greater (approximately 2 times the MRHD oral dose on a mg/m 2 basis). No effects were observed at a dose of 320 mg/kg/day (approximately one-half the MRHD dose on a mg/m 2 basis).