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  • CLASSES

    Drugs Used In Alcohol Dependence

    DEA CLASS

    Rx

    DESCRIPTION

    Oral medication adjunct to maintain abstinence in ethanol-dependent patients following ethanol withdrawal.

    COMMON BRAND NAMES

    Campral

    HOW SUPPLIED

    Acamprosate/Acamprosate Calcium/Campral Oral Tab DR: 333mg

    DOSAGE & INDICATIONS

    For the maintenance treatment of alcohol dependence.
    For use in combination with naltrexone†.
    Oral dosage
    Adults

    666 mg PO 3 times daily in combination with naltrexone (50 mg PO once daily with food). In a double-blind placebo-controlled trial, 160 patients were randomized to receive naltrexone, acamprosate, naltrexone plus acamprosate, or placebo for 12 weeks. All therapies were significantly more efficacious than placebo with regard to the primary outcomes of time to first drink, time to relapse, and cumulative abstinence. The naltrexone group tended to have a better outcome of time to first drink and time to relapse when directly compared to acamprosate. The combination of naltrexone and acamprosate demonstrated significantly lower relapse rates than placebo and acamprosate but not naltrexone. Patients received psychotherapy and psychopathologic assessments weekly throughout the treatment phase of the study.

    Oral dosage
    Adults

    666 mg PO 3 times daily is the suggested dosage. A lower dose may be effective in some patients. Lower initial doses may be required in geriatric adults since renal function may be diminished. Alternative dosage regimens have been used. In one study, doses of 1332 mg/day PO (666 mg in the morning, 333 mg at mid-day, and 333 mg in the evening) were administered for patients 60 kg or less, and doses of 1998 mg/day PO (666 mg PO 3 times daily) were administered for patients more than 60 kg. Efficacy in promoting abstinence has not been demonstrated in patients who have not undergone detoxification or achieved alcohol abstinence; therefore, acamprosate is indicated only in patients who are abstinent at the time of treatment initiation. Maintain treatment even if the patient relapses. Pharmacotherapy should be used as a part of a comprehensive management program that includes psychosocial support and treatment.

    MAXIMUM DOSAGE

    Adults

    Maximum dosage limit information is not available.

    Geriatric

    Maximum dosage limit information is not available.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    CrCl > 50 mL/min: No dosage adjustment necessary.
    CrCl 30—50 mL/min: A starting dose of 333 mg PO three times daily is recommended.
    CrCl < 30 mL/min: Use is contraindicated.

    ADMINISTRATION

    Oral Administration

    May be dosed without regard to meals; however, dosing with meals was used during clinical trials and may aide compliance in patients who regularly eat three meals daily.

    Oral Solid Formulations

    Acamprosate delayed-release tablets should be swallowed whole. Tablets are enteric-coated; do not chew, crush or cut.

    STORAGE

    Campral:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Sulfite hypersensitivity

    Contraindications include hypersensitivity to the drug. The manufacturer states that sulfites were used in the synthesis of acamprosate. Traces of residual sulfites may be present in the final drug product. Prescribers should be aware when prescribing acamprosate in patients with known sulfite hypersensitivity.

    Ethanol intoxication

    The purpose of acamprosate treatment is to help the patient abstain from ethanol; the drug should be used in conjunction with programs that provide appropriate social and mental support. Encourage patients to avoid ethanol and ethanol intoxication. However, treatment should be maintained even if the patient relapses. Clinicians should note that acamprosate does not treat ethanol withdrawal symptoms.

    Renal failure, renal impairment

    Acamprosate is contraindicated in patients with severe renal impairment or renal failure (CrCl < 30 ml/min). In patients with moderate renal impairment (CrCl of 30—50 ml/min), the manufacturer recommends a reduced starting dose (see Dosage).

    Depression, suicidal ideation

    Acamprosate should be used with caution in patients with suicidal ideation. During controlled clinical trials suicidal attempts, suicidal ideations, and completed suicides were infrequent overall but more frequent in acamprosate treated patients than those receiving placebo. Adverse events of a suicidal nature occurred in 1.4% vs. 0.5% during studies of 6 months or less duration and 2.4% vs. 0.8% in year-long studies, compared to placebo. Data from pooled studies showed 3 of 2772 (0.13%) acamprosate and 2 of 1962 (0.10%) placebo treated patients completed suicide. These events occurred during alcohol relapse but no consistent relationship to clinical course of alcohol recovery and suicidality could be identified. Caution should also be exercised in patients exhibiting depression and suicidal thinking since a widely-recognized, complex relationship between alcohol dependance, depression, and suicidality exists. Family members and caregivers of acamprosate treated patients should also be advised to monitor for and report these symptoms to the patients healthcare provider immediately.

    Pregnancy

    Acamprosate is classified as FDA pregnancy risk category C.  While the manufacturer recommends use during pregnancy only if the benefits justify the potential risk to the fetus, in women with alcoholism the risk of administering acaprosate compared to the risk of continued alcohol consumption should be taken into consideration. Animal studies have shown the drug to be teratogenic at doses comparable to the human dose on a mg/m2 basis; non-teratogenic effects on gestation have also been reported. There are no adequate and well controlled studies in pregnant women.

    Breast-feeding

    Excretion of acamprosate in human milk and its potential effects on a nursing infant are unknown. Although data during breast-feeding are limited, its use may be considered in those women requiring the drug to avoid alcohol consumption. The manufacturer recommends caution when administering to lactating women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Caution should be exercised when using acamprosate in the geriatric patient population. Plasma concentrations may be higher compared to younger patients since acamprosate is excreted unchanged in urine and that renal function may be diminished in the elderly patient population.

    Children, infants, neonates

    Safety and efficacy of acamprosate have not been established in neonates, infants, children and adolescents  less than 18 years of age.

    Driving or operating machinery

    Acamprosate may cause dizziness or impair judgment, thinking, and motor skills. Patients should use caution when driving or operating machinery until they are aware of the effects of the medication.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 0.1-1.0
    suicidal ideation / Delayed / 0.1-1.0
    cirrhosis / Delayed / 0.1-1.0
    GI bleeding / Delayed / 0.1-1.0
    hematemesis / Delayed / 0.1-1.0
    pancreatitis / Delayed / 0.1-1.0
    exfoliative dermatitis / Delayed / 0.1-1.0
    myocardial infarction / Delayed / 0.1-1.0
    bronchospasm / Rapid / 0.1-1.0
    hearing loss / Delayed / 0.1-1.0
    torticollis / Delayed / 0-0.1
    peptic ulcer / Delayed / 0-0.1
    cholecystitis / Delayed / 0-0.1
    cardiomyopathy / Delayed / 0-0.1
    heart failure / Delayed / 0-0.1
    pulmonary embolism / Delayed / 0-0.1
    visual impairment / Early / 1.0
    renal failure (unspecified) / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known

    Moderate

    depression / Delayed / 4.0-8.0
    hyperesthesia / Delayed / 0.1-1.0
    neuropathic pain / Delayed / 0.1-1.0
    hostility / Early / 0.1-1.0
    withdrawal / Early / 0.1-1.0
    hallucinations / Early / 0.1-1.0
    confusion / Early / 0.1-1.0
    migraine / Early / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    elevated hepatic enzymes / Delayed / 0.1-1.0
    vaginitis / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    phlebitis / Rapid / 0.1-1.0
    atopic dermatitis / Delayed / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    angina / Early / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    eosinophilia / Delayed / 0.1-1.0
    thrombocytopenia / Delayed / 0.1-1.0
    lymphocytosis / Delayed / 0.1-1.0
    diabetes mellitus / Delayed / 0.1-1.0
    hyperuricemia / Delayed / 0.1-1.0
    gout / Delayed / 0.1-1.0
    hyperbilirubinemia / Delayed / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    amblyopia / Delayed / 0.1-1.0
    encephalopathy / Delayed / 0-0.1
    psychosis / Early / 0-0.1
    mania / Early / 0-0.1
    hepatitis / Delayed / 0-0.1
    oral ulceration / Delayed / 0-0.1
    melena / Delayed / 0-0.1
    colitis / Delayed / 0-0.1
    nephrolithiasis / Delayed / 0-0.1
    hematuria / Delayed / 0-0.1
    ejaculation dysfunction / Delayed / 0-0.1
    psoriasis / Delayed / 0-0.1
    goiter / Delayed / 0-0.1
    hypothyroidism / Delayed / 0-0.1
    lymphadenopathy / Delayed / 0-0.1
    leukopenia / Delayed / 0-0.1
    hyponatremia / Delayed / 0-0.1
    myopathy / Delayed / 0-0.1
    photophobia / Early / 0-0.1
    ascites / Delayed / 0-0.1
    amnesia / Delayed / 1.0
    constipation / Delayed / 1.0
    impotence (erectile dysfunction) / Delayed / 1.0
    hypertension / Early / 1.0
    peripheral vasodilation / Rapid / 1.0
    chest pain (unspecified) / Early / 1.0
    palpitations / Early / 1.0
    peripheral edema / Delayed / 1.0
    dyspnea / Early / 1.0

    Mild

    diarrhea / Early / 10.0-17.0
    insomnia / Early / 6.0-9.0
    anxiety / Delayed / 5.0-8.0
    asthenia / Delayed / 5.0-7.0
    anorexia / Delayed / 2.0-5.0
    dizziness / Early / 3.0-4.0
    nausea / Early / 3.0-4.0
    flatulence / Early / 1.0-4.0
    pruritus / Rapid / 3.0-4.0
    paresthesias / Delayed / 2.0-3.0
    hyperhidrosis / Delayed / 2.0-3.0
    agitation / Early / 0.1-1.0
    vertigo / Early / 0.1-1.0
    eructation / Early / 0.1-1.0
    weight loss / Delayed / 0.1-1.0
    increased urinary frequency / Early / 0.1-1.0
    libido increase / Delayed / 0.1-1.0
    xerosis / Delayed / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    acne vulgaris / Delayed / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    ecchymosis / Delayed / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    epistaxis / Delayed / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    malaise / Early / 0.1-1.0
    fever / Early / 0.1-1.0
    paranoia / Early / 0-0.1
    hyperkinesis / Delayed / 0-0.1
    hypersalivation / Early / 0-0.1
    polyuria / Early / 0-0.1
    urinary urgency / Early / 0-0.1
    nocturia / Early / 0-0.1
    menorrhagia / Delayed / 0-0.1
    photosensitivity / Delayed / 0-0.1
    diplopia / Early / 0-0.1
    headache / Early / 1.0
    tremor / Early / 1.0
    drowsiness / Early / 1.0
    abdominal pain / Early / 1.0
    appetite stimulation / Delayed / 1.0
    dyspepsia / Early / 1.0
    weight gain / Delayed / 1.0
    vomiting / Early / 1.0
    libido decrease / Delayed / 1.0
    rash (unspecified) / Early / 1.0
    syncope / Early / 1.0
    arthralgia / Delayed / 1.0
    myalgia / Early / 1.0
    rhinitis / Early / 1.0
    cough / Delayed / 1.0
    pharyngitis / Delayed / 1.0
    dysgeusia / Early / 1.0
    chills / Rapid / 1.0
    infection / Delayed / 0.1
    back pain / Delayed / 1.0
    influenza / Delayed / 1.0

    DRUG INTERACTIONS

    Bupropion; Naltrexone: (Moderate) Naltrexone administration increases acamprosate AUC and Cmax by 25% and 33%, respectively. Monitor for acamprosate-related adverse effects. Dosage adjustments are not required, per the manufacturer.
    Naltrexone: (Moderate) Naltrexone administration increases acamprosate AUC and Cmax by 25% and 33%, respectively. Monitor for acamprosate-related adverse effects. Dosage adjustments are not required, per the manufacturer.

    PREGNANCY AND LACTATION

    Pregnancy

    Acamprosate is classified as FDA pregnancy risk category C.  While the manufacturer recommends use during pregnancy only if the benefits justify the potential risk to the fetus, in women with alcoholism the risk of administering acaprosate compared to the risk of continued alcohol consumption should be taken into consideration. Animal studies have shown the drug to be teratogenic at doses comparable to the human dose on a mg/m2 basis; non-teratogenic effects on gestation have also been reported. There are no adequate and well controlled studies in pregnant women.

    Excretion of acamprosate in human milk and its potential effects on a nursing infant are unknown. Although data during breast-feeding are limited, its use may be considered in those women requiring the drug to avoid alcohol consumption. The manufacturer recommends caution when administering to lactating women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. However, in vitro data suggests that acamprosate has affinity for type A and type B GABA receptors, however it has since been proposed that the drug lowers neuronal excitability; this action appears to be a centrally-mediated. Chronic alcohol consumption results in the up-regulation of N-methyl-D-aspartate (NMDA), an excitatory neurotransmitter of the glutamatergic system, to overcome the sedative effects of the potentiated GABAnergic system. This action allows the CNS to function more normally in a depressed state. This change in the neurotransmitter system results in anxiety, hyper-excitability and sleeplessness during alcohol withdrawal, causing the dependent patient to drink alcohol in order to relieve these symptoms. By reducing the postsynaptic efficacy of the excitatory receptors, acamprosate heightens the patients ability to remain abstinent during withdrawal. Animal studies note that the drug does not have anxiolytic, antidepressant, hypnotic, muscle relaxant, or psychotropic actions. Acamprosate reduces alcohol intake in alcohol-dependent animals in a dose-dependent manner; the effect is specific to alcohol and the mechanisms of alcohol dependence.

    PHARMACOKINETICS

    Acamprosate is administered orally. Protein binding of acamprosate is negligible and the volume of distribution is approximately 72—109 L/kg. Acamprosate does not undergo hepatic metabolism but is excreted as unchanged drug via the kidneys. The terminal half-life is approximately 20—33 hours. A linear relationship exists between creatinine clearance, total apparent plasma clearance and acamprosate half-life.

    Oral Route

    The absolute bioavailability of acamprosate is approximately 11% after oral administration. When taken with food, acamprosate Cmax and AUC are reduced by approximately 42% and 23%, respectively; however, no dose adjustment is necessary and the drug may be given with meals.