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.
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Body System/ | Number of Patients (%) with Events | |||
Acamprosate Calcium Delayed-Release Tablets 1332 mg/day | Acamprosate Calcium Delayed-Release Tablets 1998 mg/day* | Acamprosate Calcium Delayed-Release Tablets Pooled† | 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‡ | 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§ | 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 ejacul*tion, hematuria, menorrhagia, nocturia, polyuria, urinary urgency.
