ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Common adverse events that occurred in any acamprosate calcium delayed-release tablets treatment group at rate of 3% or greater and greater than the placebo group in controlled clinical trials with spontaneously reported adverse events are: accidental injury, asthenia, pain, anorexia, diarrhea, flatulence, nausea, anxiety, depression, dizziness, dry mouth, insomnia, paresthesia, pruritus and sweating (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 calcium delayed-release tablets described elsewhere in labeling include suicidality and depression and acute kidney failure[see Warnings and Precautions (5.2), and Adverse Reactions (6.2) ]. The adverse event data described below reflect the safety experience in over 7000 patients exposed to acamprosate calcium delayed-release tablets for up to one year, including over 2000 acamprosate calcium delayed-release tablets-exposed patients who participated in placebo-controlled trials.. Adverse Events Leading to Discontinuation. In placebo-controlled trials of 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 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 checklist in other studies. The overall profile of adverse events was similar using either method. Table shows those events that occurred in any acamprosate calcium delayed-release tablets treatment group at 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, 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 Rate of at Least 3% and Greater than Placebo in any Acamprosate Calcium Delayed-Release Tablets Treatment Group in Controlled Clinical Trials with Spontaneously Reported Adverse Events.Body System/Preferred TermNumber of Patients (%) with EventsAcamprosate Calcium Delayed-Release Tablets1332 mg/dayAcamprosate Calcium Delayed-Release Tablets1998 mg/dayincludes 258 patients treated with acamprosate calcium 2000 mg/day, using different dosage strength and regimen.Acamprosate Calcium Delayed-Release TabletsPooledincludes all patients in the first two columns as well as 83 patients treated with acamprosate calcium 3000 mg/day, using different dosage strength and regimen.PlaceboNumber of patients in Treatment Group397153920191706Number (%) of patients with an AE248 (62%) 910 (59%) 1231 (61%) 955 (56%)Body as Whole121 (30%) 513 (33%) 685 (34%) 517 (30%) Accidental Injuryincludes events coded as fracture by sponsor; 17 (4%) 44 (3%) 70 (3%) 52 (3%) Asthenia 29 (7%) 79 (5%) 114 (6%) 93 (5%) Pain (2%) 56 (4%) 65 (3%) 55 (3%)Digestive System 85 (21%) 440 (29%) 574 (28%) 344 (20%) Anorexia 20 (5%) 35 (2%) 57 (3%) 44 (3%) Diarrhea 39 (10%) 257 (17%) 329 (16%) 166 (10%) Flatulence (1%) 55 (4%) 63 (3%) 28 (2%) Nausea 11 (3%) 69 (4%) 87 (4%) 58 (3%)Nervous System 150 (38%) 417 (27%) 598 (30%) 500 (29%) Anxietyincludes events coded as nervousness by sponsor 32 (8%) 80 (5%) 118 (6%) 98 (6%) Depression 33 (8%) 63 (4%) 102 (5%) 87 (5%) Dizziness 15 (4%) 49 (3%) 67 (3%) 44 (3%) Dry mouth 13 (3%) 23 (1%) 36 (2%) 28 (2%) Insomnia 34 (9%) 94 (6%) 137 (7%) 121 (7%) Paresthesia 11 (3%) 29 (2%) 40 (2%) 34 (2%)Skin and Appendages 26 (7%) 150 (10%) 187 9%) 169 (10%) Pruritus 12 (3%) 68 (4%) 82 (4%) 58 (3%) Sweating 11 (3%) 27 (2%) 40 (2%) 39 (2%) 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 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 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 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.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of acamprosate calcium delayed-release tablets. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. 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 patients and is not described elsewhere in the labeling.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Dietary administration of acamprosate calcium for years to Sprague-Dawley rats at doses of 25, 100 and 400 mg/kg/day (up to 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 times the MRHD oral dose on mg/m2 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 times the MRHD oral dose on mg/m2 basis) had no effect on fertility.

CLINICAL PHARMACOLOGY SECTION.

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 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 delayed-release tablets 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 delayed-release tablets abuse or dependence.Acamprosate calcium delayed-release tablets are not known to cause alcohol aversion and does not cause disulfiram-like reaction as result of ethanol ingestion.. 12.3 Pharmacokinetics. 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 days of dosing. Steady-state peak plasma concentrations after acamprosate calcium delayed-release tablets doses of 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 L/kg). Plasma protein binding of acamprosate is negligible.. Metabolism. Acamprosate does not undergo metabolism.. Elimination. After oral dosing of 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. Gender. Acamprosate calcium delayed-release tablets do not exhibit any significant pharmacokinetic differences between male and female subjects.. Age. The pharmacokinetics of acamprosate calcium delayed-release tablets have not been evaluated in 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 delayed-release tablets have not been evaluated in pediatric population.. Renal Impairment. Peak plasma concentrations after administration of single dose of 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 linear relationship between creatinine clearance values and total apparent plasma clearance, renal clearance and plasma half-life of acamprosate. dose of x 333 mg acamprosate calcium delayed-release tablets, 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) ]. 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) ]. Hepatic Impairment. Acamprosate is not metabolized by the liver and the pharmacokinetics of acamprosate calcium delayed-release tablets are not altered in patients with mild to moderate hepatic impairment (groups and of the Child-Pugh classification). No adjustment of dosage is recommended in such patients.. Alcohol-Dependent Subjects. cross-study comparison of acamprosate calcium delayed-release tablets at doses of 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 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 33% increase in the Cmax and 25% increase in the AUC of acamprosate. No adjustment of dosage is recommended in such patients.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of acamprosate calcium delayed-release tablets in the maintenance of abstinence was supported by three clinical studies involving total of 998 patients who were administered at least one dose of acamprosate calcium delayed-release tablets or placebo as an adjunct to psychosocial therapy. Each study was 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 delayed-release tablets proved superior to placebo in maintaining abstinence, as indicated by greater percentage of subjects being assessed as continuously abstinent throughout treatment.In fourth study, the efficacy of acamprosate calcium delayed-release tablets was evaluated in alcoholics, including patients with 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 delayed-release tablets over placebo.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. oAcamprosate calcium delayed-release tablets are contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components (4.1).oAcamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (4.2).. oAcamprosate calcium delayed-release tablets are contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components (4.1).. oAcamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (4.2).. 4.1 Hypersensitivity to Acamprosate Calcium. Acamprosate calcium delayed-release tablets are contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components.. 4.2 Severe 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), Warnings and Precautions (5.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

DESCRIPTION SECTION.

11 DESCRIPTION. Acamprosate calcium is supplied in an enteric-coated tablet for oral administration. Acamprosate calcium is synthetic compound with chemical structure similar to that of the endogenous amino acid homotaurine, which is structural analogue of the amino acid neurotransmitter -aminobutyric acid and the amino acid neuromodulator taurine. Its chemical name is 3-(acetylamino)-1-propanesulfonic acid calcium salt (2:1). Its chemical formula is C10H20N2O8S2Ca and molecular weight is 400.48. Its structural formula is:Acamprosate calcium, USP is white odorless crystalline powder. It is freely soluble in water, and practically insoluble in absolute ethanol and dichloromethane.Each acamprosate calcium delayed-release tablet contains acamprosate calcium 333 mg, equivalent to 300 mg of acamprosate. Inactive ingredients in acamprosate calcium delayed-release tablets include: colloidal silicon dioxide, glyceryl behenate, hypromellose, propylene glycol, magnesium stearate, methacrylic acid copolymer type A, microcrystalline cellulose, and talc. In addition, the black imprinting ink for the tablets contains ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze. Sulfites were used in the synthesis of the drug substance and traces of residual sulfites may be present in the drug product.. Acamprosate Calcium Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dose of acamprosate calcium delayed-release tablets is two 333 mg tablets (each dose should total 666 mg) taken three times daily. 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 calcium delayed-release tablets 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 calcium delayed-release tablets should be used as part of comprehensive psychosocial treatment program.. oRecommended dose: 666 mg (two 333 mg tablets) taken three times daily (2).oDose reduction to one 333 mg tablet taken three times daily for patients with moderate renal impairment (creatinine clearance 30-50 mL/min) (2.1).oAcamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (creatinine clearance of <= 30 mL/min) (2.1, 4.2, 5.1, 8.6, 12.3).. oRecommended dose: 666 mg (two 333 mg tablets) taken three times daily (2).. oDose reduction to one 333 mg tablet taken three times daily for patients with moderate renal impairment (creatinine clearance 30-50 mL/min) (2.1).. oAcamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (creatinine clearance of <= 30 mL/min) (2.1, 4.2, 5.1, 8.6, 12.3).. 2.1 Dosage in Renal Impairment. For patients with moderate renal impairment (creatinine clearance of 30-50 mL/min), starting dose of one 333 mg tablet taken three times daily is recommended. Acamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (creatinine clearance of <= 30 mL/min) [see Contraindications (4.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) ].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Acamprosate Calcium Delayed-Release Tablets are available containing 333 mg of acamprosate calcium, USP (equivalent to 300 mg of acamprosate). oThe 333 mg tablets are white, enteric-coated, round, unscored tablets imprinted with over AC in black ink on one side of the tablet and blank on the other side.. oThe 333 mg tablets are white, enteric-coated, round, unscored tablets imprinted with over AC in black ink on one side of the tablet and blank on the other side.. Enteric-coated tablets, 333 mg (3).

DRUG INTERACTIONS SECTION.

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) ].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Forty-one of the 4234 patients in double-blind, placebo-controlled, clinical trials of acamprosate calcium delayed-release tablets 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) ].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Acamprosate Calcium Delayed-Release Tablets are available containing 333 mg of acamprosate calcium, USP (equivalent to 300 mg of acamprosate). The 333 mg tablets are white, enteric-coated, round, unscored tablets imprinted with over AC in black ink on one side of the tablet and blank on the other side. They are available as follows:NDC 0378-6333-80bottles of 180 tabletsStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Acamprosate calcium delayed-release tablets are indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. Treatment with acamprosate calcium delayed-release tablets should be part of comprehensive management program that includes psychosocial support.The efficacy of acamprosate calcium delayed-release tablets in promoting abstinence has not been demonstrated in subjects who have not undergone detoxification and not achieved alcohol abstinence prior to beginning acamprosate calcium delayed-release tablets treatment. The efficacy of acamprosate calcium delayed-release tablets in promoting abstinence from alcohol in polysubstance abusers has not been adequately assessed.. oAcamprosate calcium delayed-release tablets are indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation (1, 14).oTreatment with acamprosate calcium delayed-release tablets should be part of comprehensive management program that includes psychosocial support (1).. oAcamprosate calcium delayed-release tablets are indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation (1, 14).. oTreatment with acamprosate calcium delayed-release tablets should be part of comprehensive management program that includes psychosocial support (1).

INFORMATION FOR PATIENTS SECTION.

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. 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 patients 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. oAdvise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.oAdvise patients to notify their physician if they are breast feeding.. oAdvise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.. oAdvise patients to notify their physician if they are breast feeding.. Relapse to Drinking. oAdvise 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.oAdvise patients that acamprosate calcium delayed-release tablets have been shown to help maintain abstinence only when used as part of 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--500 096, IndiaRevised: 7/2019MX:ACMPDR:R775068772. oAdvise 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.. oAdvise patients that acamprosate calcium delayed-release tablets have been shown to help maintain abstinence only when used as part of treatment program that includes counseling and support.

LABOR & DELIVERY SECTION.

8.2 Labor and Delivery. The potential for acamprosate calcium delayed-release tablets to affect the duration of labor and delivery is unknown.

MECHANISM OF ACTION SECTION.

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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Dietary administration of acamprosate calcium for years to Sprague-Dawley rats at doses of 25, 100 and 400 mg/kg/day (up to 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 times the MRHD oral dose on mg/m2 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 times the MRHD oral dose on mg/m2 basis) had no effect on fertility.

NONTERATOGENIC EFFECTS SECTION.

Nonteratogenic Effects. 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 times the MRHD oral dose on mg/m2 basis). No effects were observed at dose of 320 mg/kg/day (approximately one-half the MRHD dose on mg/m2 basis).

NURSING MOTHERS SECTION.

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 acamprosate calcium delayed-release tablets are administered to nursing woman.

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 333 mg NDC 0378-6333-80Acamprosate CalciumDelayed-ReleaseTablets333 mgRx only 180 TabletsEach enteric-coated tablet contains333 mg of acamprosate calcium(equivalent to 300 mg of acamprosate).Usual Dosage: See accompanyingprescribing information.Keep this and all medication out ofthe reach of children.Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in IndiaMylan.comRMX6333SS3Dispense in tight, light-resistantcontainer as defined in the USPusing child-resistant closure.Keep container tightly closed.Code No.: MH/DRUGS/25/NKD/89. Acamprosate Calcium Delayed-Release Tablets 333 mg Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of acamprosate calcium delayed-release tablets have not been established in the pediatric population.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Pharmacodynamic studies have shown that acamprosate calcium reduces alcohol intake in alcohol-dependent animals in 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 delayed-release tablets 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 delayed-release tablets abuse or dependence.Acamprosate calcium delayed-release tablets are not known to cause alcohol aversion and does not cause disulfiram-like reaction as result of ethanol ingestion.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. 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 days of dosing. Steady-state peak plasma concentrations after acamprosate calcium delayed-release tablets doses of 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 L/kg). Plasma protein binding of acamprosate is negligible.. Metabolism. Acamprosate does not undergo metabolism.. Elimination. After oral dosing of 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. Gender. Acamprosate calcium delayed-release tablets do not exhibit any significant pharmacokinetic differences between male and female subjects.. Age. The pharmacokinetics of acamprosate calcium delayed-release tablets have not been evaluated in 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 delayed-release tablets have not been evaluated in pediatric population.. Renal Impairment. Peak plasma concentrations after administration of single dose of 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 linear relationship between creatinine clearance values and total apparent plasma clearance, renal clearance and plasma half-life of acamprosate. dose of x 333 mg acamprosate calcium delayed-release tablets, 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) ]. 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) ]. Hepatic Impairment. Acamprosate is not metabolized by the liver and the pharmacokinetics of acamprosate calcium delayed-release tablets are not altered in patients with mild to moderate hepatic impairment (groups and of the Child-Pugh classification). No adjustment of dosage is recommended in such patients.. Alcohol-Dependent Subjects. cross-study comparison of acamprosate calcium delayed-release tablets at doses of 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 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 33% increase in the Cmax and 25% increase in the AUC of acamprosate. No adjustment of dosage is recommended in such patients.

PREGNANCY SECTION.

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 mg/m2 basis) and in rabbits when given in doses that are approximately times the human dose (on mg/m2 basis). Acamprosate calcium produced 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 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 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 times the MRHD oral dose on mg/m2 basis). No developmental effects were observed in New Zealand white rabbits at oral doses up to 1000 mg/kg/day (approximately times the MRHD oral dose on 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. Acamprosate calcium delayed-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nonteratogenic Effects. 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 times the MRHD oral dose on mg/m2 basis). No effects were observed at dose of 320 mg/kg/day (approximately one-half the MRHD dose on mg/m2 basis).

SPL UNCLASSIFIED SECTION.

2.1 Dosage in Renal Impairment. For patients with moderate renal impairment (creatinine clearance of 30-50 mL/min), starting dose of one 333 mg tablet taken three times daily is recommended. Acamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (creatinine clearance of <= 30 mL/min) [see Contraindications (4.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) ].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPregnancy: Acamprosate calcium delayed-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (8.1).oNursing Mothers: Caution should be exercised when acamprosate calcium delayed-release tablets are administered to nursing woman (8.3).oRenal Impairment: Dose reduction required for moderate renal impairment; contraindicated in severe renal impairment (2.1, 4.2, 5.1, 8.6, 12.3). oPregnancy: Acamprosate calcium delayed-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (8.1).. oNursing Mothers: Caution should be exercised when acamprosate calcium delayed-release tablets are administered to nursing woman (8.3).. oRenal Impairment: Dose reduction required for moderate renal impairment; contraindicated in severe renal impairment (2.1, 4.2, 5.1, 8.6, 12.3). 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 mg/m2 basis) and in rabbits when given in doses that are approximately times the human dose (on mg/m2 basis). Acamprosate calcium produced 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 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 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 times the MRHD oral dose on mg/m2 basis). No developmental effects were observed in New Zealand white rabbits at oral doses up to 1000 mg/kg/day (approximately times the MRHD oral dose on 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. Acamprosate calcium delayed-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nonteratogenic Effects. 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 times the MRHD oral dose on mg/m2 basis). No effects were observed at dose of 320 mg/kg/day (approximately one-half the MRHD dose on mg/m2 basis).. 8.2 Labor and Delivery. The potential for acamprosate calcium delayed-release tablets 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 acamprosate calcium delayed-release tablets are administered to nursing woman.. 8.4 Pediatric Use. The safety and efficacy of acamprosate calcium delayed-release tablets 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 acamprosate calcium delayed-release tablets 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. 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 Clinical Pharmacology (12.3) ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Contains sodium sulfite, sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.. oDose reduction is required for patients with moderate renal impairment (5.1).oMonitor patients for depression or suicidal ideation and prompt patients, families, and caregivers to report such symptoms to the health care provider (5.2).. oDose reduction is required for patients with moderate renal impairment (5.1).. oMonitor patients for depression or suicidal ideation and prompt patients, families, and caregivers to report such symptoms to the health care provider (5.2).. 5.1 Renal Impairment. Treatment with acamprosate calcium delayed-release tablets in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) requires dose reduction[see Dosage and Administration (2.1) ]. 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), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) ]. 5.2 Suicidality and Depression. In controlled clinical trials of acamprosate calcium delayed-release tablets, adverse events of suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in acamprosate calcium delayed-release tablets-treated patients than in patients treated with placebo (1.4% vs. 0.5% in studies of months or less; 2.4% vs. 0.8% in year-long studies). Completed suicides occurred in of 2272 (0.13%) patients in the pooled acamprosate group from all controlled studies and of 1962 patients (0.10%) in the placebo group. Adverse events coded as depression were reported at similar rates in acamprosate calcium delayed-release tablets-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 calcium delayed-release tablets, should be monitored for the development of symptoms of depression or suicidal thinking. 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 patients health care provider.. 5.3 Alcohol Withdrawal. Use of acamprosate calcium delayed-release tablets does not eliminate or diminish withdrawal symptoms.

TERATOGENIC EFFECTS SECTION.

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 mg/m2 basis) and in rabbits when given in doses that are approximately times the human dose (on mg/m2 basis). Acamprosate calcium produced 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 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 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 times the MRHD oral dose on mg/m2 basis). No developmental effects were observed in New Zealand white rabbits at oral doses up to 1000 mg/kg/day (approximately times the MRHD oral dose on 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. Acamprosate calcium delayed-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.