6 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 / dayincludes 258 patients treated with acamprosate calcium 2000 mg/day, using a different dosage strength and regimen. Acamprosate Calcium Pooledincludes 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 Injuryincludes 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 %) Anxietyincludes 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 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, 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. 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-US Postmarketing Evaluation of Acamprosate Calcium The serious adverse event of acute kidney failure has been reported to be temporally associated with acamprosate calcium treatment in at least 3 patients and is not described elsewhere in the labeling.