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Acamprosate Calcium Delayed-Release Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Acamprosate calcium is supplied in an enteric-coated tablet for oral administration. Acamprosate calcium is a synthetic compound with a chemical structure similar to that of the endogenous amino acid homotaurine, which is a structural analogue of the amino acid neurotransmitter γ-aminobutyric acid and the amino acid neuromodulator taurine. Its chemical name is calcium acetylaminopropane sulfonate. Its chemical formula is C10H20N2O8S2Ca and molecular weight is 400.48. Its structural formula is:

Acamprosate calcium is a white, odorless or nearly odorless powder. It is freely soluble in water, and practically insoluble in absolute ethanol and dichloromethane.

Each acamprosate tablet contains acamprosate calcium 333 mg, equivalent to 300 mg of acamprosate. Inactive ingredients in acamprosate tablets include: crospovidone, microcrystalline cellulose, magnesium silicate, sodium starch glycolate, colloidal anhydrous silica, magnesium stearate, talc, propylene glycol and Eudragit® L 30 D or equivalent. Sulfites were used in the synthesis of the drug substance and traces of residual sulfites may be present in the drug product.

2. INDICATIONS AND USAGE

Acamprosate is indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. Treatment with acamprosate should be part of a comprehensive management program that includes psychosocial support.

The efficacy of acamprosate in promoting abstinence has not been demonstrated in subjects who have not undergone detoxification and not achieved alcohol abstinence prior to beginning acamprosate treatment. The efficacy of acamprosate in promoting abstinence from alcohol in polysubstance abusers has not been adequately assessed.

3. DOSAGE AND ADMINISTRATION

The recommended dose of acamprosate 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 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 should be used as part of a comprehensive psychosocial treatment program.

3.1 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 is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min) [see Contraindications, Warnings and Precautions, Use in Specific Populations].

4. CONTRAINDICATIONS

4.1 Hypersensitivity to Acamprosate Calcium

Acamprosate is contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components.

4.2 Severe Renal Impairment

Acamprosate is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min) [see Dosage and Administration, Warnings and Precautions, Use in Specific Populations].

5. 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. In vitro and in vivo 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in 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/m2 basis) and in rabbits when given in doses that are approximately 3 times the human dose (on a mg/m2 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 oral dose on a mg/m2 basis). The malformations included hydronephrosis, malformed iris, retinal dysplasia, and retroesophageal subclavian artery. 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

6.2 Labor and Delivery

The potential for acamprosate to affect the duration of labor and delivery is unknown.

6.3 Nursing Mothers

In animal studies, acamprosate was excreted in the milk of lactating rats dosed orally with acamprosate calcium. The concentration of acamprosate in milk compared to blood was 1.3:1. It is not known whether acamprosate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when acamprosate is administered to a nursing woman.

6.4 Pediatric Use

The safety and efficacy of acamprosate have not been established in the pediatric population.

6.5 Geriatric Use

Forty-one of the 4234 patients in double-blind, placebo-controlled, clinical trials of acamprosate were 65 years of age or older, while none were 75 years of age or over. There were too few patients in the ≥65 age group to evaluate any differences in safety or effectiveness for geriatric patients compared to younger patients.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (See ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).

6.6 Renal Impairment

Acamprosate is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min) [see Dosage and Administration, Contraindications, Warnings and Precautions].

7. WARNINGS AND PRECAUTIONS

7.1 Renal Impairment

Treatment with acamprosate in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) requires a dose reduction [see Dosage and Administration]. Acamprosate is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min) [see Dosage and Administration , Contraindications, Use in Specific Populations].

7.2 Suicidality and Depression

In controlled clinical trials of acamprosate, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in acamprosate-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-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, should be monitored for the development of symptoms of depression or suicidal thinking. Families and caregivers of patients being treated with acamprosate 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.

7.3 Alcohol Withdrawal

Use of acamprosate does not eliminate or diminish withdrawal symptoms.

8. ADVERSE REACTIONS

8.1 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 described elsewhere in labeling include suicidality and depression and acute kidney failure [see Warnings and Precautions, and Adverse Reactions].

The adverse event data described below reflect the safety experience in over 7000 patients exposed to acamprosate for up to one year, including over 2000 acamprosate-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-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-treated patients. Only diarrhea was associated with the discontinuation of more than 1% of patients (2% of acamprosate-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-treated patients than in placebo-treated patients.

Common Adverse Events Reported in Controlled Trials

Common, non-serious 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 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 Treatment Group in Controlled Clinical Trials with Spontaneously Reported Adverse Events

* includes events coded as “fracture” by sponsor; **includes events coded as “nervousness” by sponsor

1 includes 258 patients treated with acamprosate calcium 2000 mg/day, using a different dosage strength and regimen.

2 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.

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Concomitant Therapies

In clinical trials, the safety profile in subjects treated with acamprosate 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 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

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

8.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of acamprosate. 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 treatment in at least 3 patients and is not described elsewhere in the labeling.

9. OVERDOSAGE

In all reported cases of acute overdosage with acamprosate (total reported doses of up to 56 grams of acamprosate calcium), the only symptom that could be reasonably associated with acamprosate was diarrhea. Hypercalcemia has not been reported in cases of acute overdose. A risk of hypercalcemia should be considered in chronic overdosage only. Treatment of overdose should be symptomatic and supportive.

10. 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.

11. PHARMACOKINETICS

Absorption

The absolute bioavailability of acamprosate 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 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 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.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: CAMPRAL, by FOREST PHARM.

b) Generic drugs: None.

2) How Supplied:

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

Opaque HDPE bottles of 180-NDC #0456-3330-01

3) Storage:

Store at 25ºC (77ºF); excursions permitted to 15º - 30ºC (59º - 86ºF).

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Rev 01/12