Campral (Page 2 of 3)

6.2 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.

Serious Adverse Events Observed During the Non-US Postmarketing Evaluation of Campral (acamprosate calcium)

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.

7 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 [see Clinical Pharmacology (12.3) ].

8 USE IN SPECIFIC POPULATIONS

8.1 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 (MRHD) oral dose on a mg/m2 basis). The malformations included hydronephrosis, malformed iris, retinal dysplasia, and retroesophageal subclavian artery. No findings were observed at an oral dose of 50 mg/kg/day (approximately one-fifth the MRHD oral dose on a mg/m2 basis). An increased incidence of hydronephrosis was also noted in Burgundy Tawny rabbits at oral doses of 400 mg/kg/day or greater (approximately 3 times the MRHD oral dose on a mg/m2 basis). No developmental effects were observed in New Zealand white rabbits at oral doses up to 1000 mg/kg/day (approximately 8 times the MRHD oral dose on a mg/m2 basis). 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. Campral should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic effects: A study conducted in pregnant mice that were administered acamprosate calcium by the oral route starting on Day 15 of gestation through the end of lactation on postnatal day 28 demonstrated an increased incidence of still-born fetuses at doses of 960 mg/kg/day or greater (approximately 2 times the MRHD oral dose on a mg/m2 basis). No effects were observed at a dose of 320 mg/kg/day (approximately one-half the MRHD dose on a mg/m2 basis).

8.2 Labor and Delivery

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

8.3 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 Campral is administered to a nursing woman.

8.4 Pediatric Use

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

8.5 Geriatric Use

Forty-one of the 4234 patients in double-blind, placebo-controlled, clinical trials of Campral 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 Clinical Pharmacology (12.3), Adverse Reactions (6.1), and Dosage and Administration (2.1) ].

8.6 Renal Impairment

Campral is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min) [s ee Dosage and Administration (2.1), Contraindications (4.2), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

In all reported cases of acute overdosage with Campral (total reported doses of up to 56 grams of acamprosate calcium), the only symptom that could be reasonably associated with Campral 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.

11 DESCRIPTION

Campral (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 C10 H20 N2 O8 S2 Ca and molecular weight is 400.48. Its structural formula is:

Structural Formula

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 Campral tablet contains acamprosate calcium 333 mg, equivalent to 300 mg of acamprosate. Inactive ingredients in Campral 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.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Pharmacodynamic studies have shown that acamprosate calcium reduces alcohol intake in alcohol-dependent 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.

12.3 Pharmacokinetics

Absorption

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.

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 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 (8.6) ].

Campral is 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) ].

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 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 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 co-administration 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.

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