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.

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.

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.

Pregnancy Category C

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 Cmax 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

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 Cmax and a 25% increase in the AUC of acamprosate. No adjustment of dosage is recommended in such patients.

Renal Impairment

A lower dose is recommended for patients with moderate 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), Contraindications (4.2), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Suicidality and Depression

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 [see Warnings and Precautions (5.2)].

Alcohol Withdrawal

Use of acamprosate calcium delayed-release tablets does not eliminate or diminish withdrawal symptoms [see Warnings and Precautions (5.3)].

Pregnancy and Breast Feeding

• Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.
• Advise patients to notify their physician if they are breast feeding.

Relapse to Drinking

• Advise patients to continue acamprosate calcium delayed-release tablets therapy as directed, even in the event of relapse and remind them to discuss any renewed drinking with their physicians.
• Advise patients that acamprosate calcium delayed-release tablets have been shown to help maintain abstinence only when used as a part of a treatment program that includes counseling and support.

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Manufactured by:
Mylan Laboratories Limited
Hyderabad—500 096, India

Revised: 11/2022
MX:ACMPDR:R8

75094413