Acamprosate Calcium

General

Initiate therapy as soon as possible after the patient has achieved abstinence from alcohol ingestion.1

Therapy can be continued even if the patient relapses.1

Administration

Oral Administration

Administer orally 3 times daily without regard to meals.1 For individuals who regularly eat 3 meals a day, administer with meals (to improve compliance).1

Dosage

Available as acamprosate calcium; dosage expressed in terms of the salt.1

Adults

666 mg 3 times daily.1

A lower dosage (1.3 grams daily given in 3 unequally divided doses of 666, 333, and 333 mg) also evaluated in clinical studies and may be effective in some patients.1 2 3 4 11

Special Populations

Hepatic Impairment

Dosage adjustment not required in patients with mild to moderate hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

In patients with moderate renal impairment (Clcr 30–50 mL/minute), 333 mg 3 times daily.1 (See Renal Impairment under Cautions.)

Do not use in patients with severe renal impairment (Clcr<30 mL/minute).1 (See Contraindications under Cautions.)

Geriatric Patients

Select dosage carefully.1 (See Geriatric Use under Cautions.)

Storage

Oral

25°C (may be exposed to 15–30°C).1

Dosage Forms And Strengths

Campral 333 mg tablets are enteric-coated, white, round, biconvex tablets, identified with “333” debossed on one side.

NDC:68151-4760-0 in a PACKAGE of 1 TABLET, DELAYED RELEASES

Storage And Handling

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Manufactured by: Merck Santé s.a.s. Subsidiary of Merck KGaA, Darmstadt, Germany 37, rue Saint- Romain 69008 LYON FRANCE. Manufactured for: Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO, 63045. Revised: Aug 2014

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 Campral described elsewhere in labeling include suicidality and depression and acute kidney failure [see WARNINGS AND PRECAUTIONS]

The adverse event data described below reflect the safety experience in over 7000 patients exposed to Campral for up to one year, including over 2000 Campral-exposed patients who participated in placebocontrolled trials.

In placebo-controlled trials of 6 months or less, 8% of Campral-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 Campral-treated patients. Only diarrhea was associated with the discontinuation of more than 1% of patients (2% of Campral-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 Campral-treated patients than in placebo-treated patients.

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. shows those events that occurred in any Campral 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 Campral Treatment Group in Controlled Clinical Trials with Spontaneously Reported Adverse Events

In clinical trials, the safety profile in subjects treated with Campral 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 Campral concomitantly with antidepressants more commonly reported both weight gain and weight loss, compared with patients taking either medication alone.

Following is a list of terms that reflect treatment-emergent adverse events reported by patients treated with Campral in 20 clinical trials (4461 patients treated with Campral, 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Campral. 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.

The serious adverse event of acute kidney failure has been reported to be temporally associated with Campral treatment in at least 3 patients and is not described elsewhere in the labeling.

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. and 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. In vitroin vivo

Pharmacodynamics

Pharmacodynamic studies have shown that acamprosate calcium reduces alcohol intake in alcoholdependent animals in a dose-dependent manner and that this effect appears to be specific to alcohol and the mechanisms of alcohol dependence.

Acamprosate calcium has negligible observable central nervous system (CNS) activity in animals outside of its effects on alcohol dependence, exhibiting no anticonvulsant, antidepressant, or anxiolytic activity.

The administration of acamprosate calcium is not associated with the development of tolerance or dependence in animal studies. Campral did not produce any evidence of withdrawal symptoms in patients in clinical trials at therapeutic doses. Post marketing data, collected retrospectively outside the U.S. have provided no evidence of Campral abuse or dependence.

Campral is not known to cause alcohol aversion and does not cause a disulfiram-like reaction as a result of ethanol ingestion.

Pharmacokinetics

The absolute bioavailability of Campral 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 Campral doses of 2 x 333 mg tablets three times daily average 350 ng/mL and occur at 3-8 hours post-dose. Coadministration of Campral 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.

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.

Acamprosate does not undergo metabolism.

After oral dosing of 2 x 333 mg of Campral, the terminal half-life ranges from approximately 20-33 hours. Following oral administration of Campral, the major route of excretion is via the kidneys as acamprosate.

Special Populations

Gender: Campral does not exhibit any significant pharmacokinetic differences between male and female subjects.

Age: The pharmacokinetics of Campral have not been evaluated in a geriatric population. However, since renal function diminishes in elderly patients and acamprosate is excreted unchanged in urine, acamprosate plasma concentrations are likely to be higher in the elderly population compared to younger adults.

Pediatrics: The pharmacokinetics of Campral have not been evaluated in a pediatric population.

Renal Impairment : Peak plasma concentrations after administration of a single dose of 2 x 333 mg Campral tablets to patients with moderate or severe renal impairment were about 2-fold and 4-fold higher, respectively, compared to healthy subjects. Similarly, elimination half-life was about 1.8-fold and 2.6-fold longer, respectively, compared to healthy subjects. There is a linear relationship between creatinine clearance values and total apparent plasma clearance, renal clearance and plasma half-life of acamprosate. A dose of 1 x 333 mg Campral, three times daily, is recommended in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min, [see Use in Specific Populations]

Campral is contraindicated in patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min). [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and Use in Specific Populations]

Hepatic Impairment: Acamprosate is not metabolized by the liver and the pharmacokinetics of Campral are not altered in patients with mild to moderate hepatic impairment (groups A and B of the Child-Pugh classification). No adjustment of dosage is recommended in such patients.

Alcohol-dependent subjects: A cross-study comparison of Campral at doses of 2 x 333 mg three times daily indicated similar pharmacokinetics between alcohol-dependent subjects and healthy subjects.

Drug-Drug Interactions

Acamprosate had no inducing potential on the cytochrome CYP1A2 and 3A4 systems, and inhibition studies suggest that acamprosate does not inhibit metabolism mediated by cytochrome CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. The pharmacokinetics of Campral 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 coadministration with Campral. However, co-administration of Campral 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.

Clinical Studies

The efficacy of Campral in the maintenance of abstinence was supported by three clinical studies involving a total of 998 patients who were administered at least one dose of Campral or placebo as an adjunct to psychosocial therapy. Each study was a double-blind, placebo-controlled trial in alcoholdependent patients who had undergone inpatient detoxification and were abstinent from alcohol on the day of randomization. Study durations ranged from 90 days to 360 days. Campral proved superior to placebo in maintaining abstinence, as indicated by a greater percentage of subjects being assessed as continuously abstinent throughout treatment.

In a fourth study, the efficacy of Campral was evaluated in alcoholics, including patients with a history of polysubstance abuse and patients who had not undergone detoxification and were not required to be abstinent at baseline. This study failed to demonstrate superiority of Campral over placebo.

Acamprosate affects chemicals in the brain that may become unbalanced in a person who is addicted to alcohol. Acamprosate works by restoring this chemical balance in the brain in an alcohol-dependent person who has recently quit drinking.

Acamprosate is used to help a person who has recently quit drinking alcohol continue to choose not to drink (remain abstinent from alcohol). It is used together with behavior modification and counseling support to help you stop drinking.

Acamprosate is not likely to be helpful to a person who has not already quit drinking or undergone detoxification. It may not be helpful to a person who is also addicted to other substances besides alcohol.

Acamprosate may also be used for other purposes not listed in this medication guide.

• Alcoholism