Acamprosate Calcium: Package Insert and Label Information (Page 3 of 3)

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. Acamprosate calcium 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 acamprosate calcium abuse or dependence.

Acamprosate calcium 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 acamprosate calcium 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 doses of 2 x 333 mg tablets three times daily average 350 ng/mL and occur at 3 to 8 hours post-dose. Coadministration of acamprosate calcium with food decreases bioavailability as measured by C max 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 to 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, the terminal half-life ranges from approximately 20 to 33 hours. Following oral administration of acamprosate calcium, the major route of excretion is via the kidneys as acamprosate.

Special Populations

Gender

Acamprosate calcium does not exhibit any significant pharmacokinetic differences between male and female subjects.

Age

The pharmacokinetics of acamprosate calcium 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 acamprosate calcium have not been evaluated in a pediatric population.

Renal Impairment

Peak plasma concentrations after administration of a single dose of 2 x 333 mg acamprosate calcium delayed-release 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 acamprosate calcium, three times daily, is recommended in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min [see Use in Specific Populations (8.6)].

Acamprosate calcium 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 acamprosate calcium 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 acamprosate calcium 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 acamprosate calcium were unaffected when coadministered 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 acamprosate calcium. However, coadministration of acamprosate calcium with naltrexone led to a 33% increase in the C max and a 25% increase in the AUC of acamprosate. No adjustment of dosage is recommended in such patients.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dietary administration of acamprosate calcium for 2 years to Sprague-Dawley rats at doses of 25, 100 and 400 mg/kg/day (up to 3 times the maximum recommended human daily (MRHD) oral dose on an AUC basis) and CD-1 mice at doses of 400, 1200 and 3600 mg/kg/day (up to 25 times the MRHD on an AUC basis) showed no evidence of increased tumor incidence.

Acamprosate calcium was negative in all genetic toxicology studies conducted. Acamprosate calcium demonstrated no evidence of genotoxicity in an in vitro bacterial reverse point mutation assay (Ames assay) or an in vitro mammalian cell gene mutation test using Chinese Hamster Lung V79 cells. No clastogenicity was observed in an in vitro chromosomal aberration assay in human lymphocytes and no chromosomal damage detected in an in vivo mouse micronucleus assay.

Acamprosate calcium had no effect on fertility after treatment for 70 days prior to mating in male rats and for 14 days prior to mating, throughout mating, gestation and lactation in female rats at doses up to 1000 mg/kg/day (approximately 4 times the MRHD oral dose on a mg/m 2 basis). In mice, acamprosate calcium administered orally for 60 days prior to mating and throughout gestation in females at doses up to 2400 mg/kg/day (approximately 5 times the MRHD oral dose on a mg/m 2 basis) had no effect on fertility.

14 CLINICAL STUDIES

The efficacy of acamprosate 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 acamprosate calcium or placebo as an adjunct to psychosocial therapy. Each study was a double-blind, placebo-controlled trial in alcohol-dependent 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. Acamprosate calcium 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 acamprosate calcium 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 acamprosate calcium over placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Acamprosate Calcium Delayed-release Tablets are available containing 333 mg of acamprosate calcium.

The 333 mg tablet is a white enteric-coated, round, unscored tablet imprinted with M over AC in black ink on one side of the tablet and blank on the other side. They are available as follows:

NDC 51079-241-06 – Unit dose blister packages of 50 (5 cards of 10 tablets each).

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

17 PATIENT COUNSELING INFORMATION

17.1 Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe acamprosate calcium delayed-release tablets.

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 has 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 in India by:
Mylan Laboratories Limited
Hyderabad—500 034, India
Code No.: MH/DRUGS/25/NKD/89

Distributed by:
Mylan Institutional Inc.
Rockford, IL 61103 U.S.A.

S-12246
9/15

PRINCIPAL DISPLAY PANEL — 333 mg

NDC 51079-241-06

Acamprosate
Calcium
Delayed-Release
Tablets
333 mg

50 Tablets (5 x 10)

Each enteric-coated tablet contains
333 mg of acamprosate calcium
(equivalent to 300 mg of acamprosate).

Usual Dosage: See accompanying
prescribing information.

Store at 20° to 25°C (68° to 77°F). [See
USP Controlled Room Temperature.]

Code No.: MH/DRUGS/25/NKD/89

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

Made in India

Rx only

S-11940 R1

Distributed by:

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

Acamprosate Calcium Delayed-Release 333 mg Tablets Unit Carton Label
(click image for full-size original)
Unit Carton & Serialized Flap
(click image for full-size original)
ACAMPROSATE CALCIUM acamprosate calcium enteric-coated tablet, delayed release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51079-241(NDC:0378-6333)
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ACAMPROSATE CALCIUM (ACAMPROSATE) ACAMPROSATE CALCIUM 333 mg
Inactive Ingredients
Ingredient Name Strength
AMMONIA
FERROSOFERRIC OXIDE
SILICON DIOXIDE
GLYCERYL DIBEHENATE
HYPROMELLOSE, UNSPECIFIED
MAGNESIUM STEARATE
METHACRYLIC ACID — METHYL METHACRYLATE COPOLYMER (1:1)
MICROCRYSTALLINE CELLULOSE
PROPYLENE GLYCOL
SHELLAC
TALC
Product Characteristics
Color white Score no score
Shape ROUND Size 10mm
Flavor Imprint Code M;AC
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:51079-241-06 50 BLISTER PACK in 1 CARTON contains a BLISTER PACK (51079-241-01)
1 NDC:51079-241-01 1 TABLET, DELAYED RELEASE in 1 BLISTER PACK This package is contained within the CARTON (51079-241-06)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200142 07/16/2013 04/30/2021
Labeler — Mylan Institutional Inc. (039615992)

Revised: 06/2020 Mylan Institutional Inc.

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